Clinical Pharmacokinetics of Ibuprofen: The First 30 Years

DRUG DISPOSITION Clin Pharmacokinet 1998 Feb; 34 (2): 101-154
0312-5963/98/0002-0101/$27.00/0
© Adis International Limited. All rights reserved.
Clinical Pharmacokinetics of Ibuprofen

The First 30 Years
Neal M. Davies
Faculty of Medicine, Department of Pharmacology and Therapeutics, University of Calgary,
Calgary, Alberta, Canada
Contents
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
1. Analytical Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
2. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
2.1 Oral Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
2.2 Topical Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
2.3 Inversion and Stereoisomerism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
2.4 Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
2.5 Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
2.6 Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
3. Implications of Pharmacokinetic Properties for Therapeutic Use . . . . . . . . . . . . . . . . . . . 135
3.1 Rationale for Development of Stereochemically Pure S-Ibuprofen . . . . . . . . . . . . . . . 135
3.2 Dose and Therapeutic Range . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
3.3 Disease and the Pharmacokinetics of Ibuprofen . . . . . . . . . . . . . . . . . . . . . . . . . . 139
3.4 Influence of Age on the Pharmacokinetics of Ibuprofen . . . . . . . . . . . . . . . . . . . . . 141
4. Pharmacokinetic Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
4.1 Effect of Other Drugs on the Pharmacokinetics of Ibuprofen . . . . . . . . . . . . . . . . . . . 142
4.2 Effect of Ibuprofen on the Pharmacokinetics of Other Drugs . . . . . . . . . . . . . . . . . . . 144
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
Summary Ibuprofen is a chiral nonsteroidal anti-inflammatory drug (NSAID) of the 2

arylpropionic acid (2-APA) class. A common structural feature of 2-APA NSAIDs
is a sp3-hybridised tetrahedral chiral carbon atom within the propionic acid side
chain moiety with the S-(+)-enantiomer possessing most of the beneficial anti-
inflammatory activity. Ibuprofen demonstrates marked stereoselectivity in its
pharmacokinetics. Substantial unidirectional inversion of the R-(–) to the S-(+)
enantiomer occurs and thus, data generated using nonstereospecific assays may
not be extrapolated to explain the disposition of the individual enantiomers.
The absorption of ibuprofen is rapid and complete when given orally. The
area under the plasma concentration-time curve (AUC) of ibuprofen is dose-
dependent. Ibuprofen binds extensively, in a concentration-dependent manner, to
plasma albumin. At doses greater than 600mg there is an increase in the unbound
fraction of the drug, leading to an increased clearance of ibuprofen and a reduced
AUC of the total drug. Substantial concentrations of ibuprofen are attained in
synovial fluid, which is a proposed site of action for nonsteroidal anti-inflammatory
drugs.
102 Davies
Ibuprofen is eliminated following biotransformation to glucuronide conjugate

metabolites that are excreted in urine, with little of the drug being eliminated
unchanged. The excretion of conjugates may be tied to renal function and the
accumulation of conjugates occurs in end-stage renal disease. Hepatic disease
and cystic fibrosis can alter the disposition kinetics of ibuprofen. Ibuprofen is not
excreted in substantial concentrations into breast milk.
Significant drug interactions have been demonstrated for aspirin (acetylsali-
cylic acid), cholestyramine and methotrexate. A relationship between ibuprofen
plasma concentrations and analgesic and antipyretic effects has been elucidated.
Ibuprofen, (±)-(R,S)-2-(4-isobutylphenyl)-pro- currently used chiral NSAIDs, its anti-inflammatory

pionic acid (fig. 1), is a chiral 2-arylpropionic acid activity has been attributed almost entirely to the
(2-APA) derivative nonsteroidal anti-inflamma- S-(+)-enantiomer, and stereoselective pharmacoki-
tory drug (NSAID). Ibuprofen was developed as an netics have been extensively studied.[4] General re-
antirheumatic drug in the 1960s[1] and has been view articles are available which deals with the
widely used as a prescription drug in Great Britain pharmacological and therapeutic uses of ibuprofen,
since 1967 and since 1974 in the US. Ibuprofen however, the issue of chirality has been ignored.[7,8]
became available without a prescription in the US In this article the first 30 years of the clinical phar-
and the UK in 1984. macokinetics of ibuprofen and its enantiomers are
Ibuprofen is a potent inhibitor of prostaglandin updated and reviewed. Unless otherwise stated, all
synthesis with the S-(+)-enantiomer possessing the doses throughout the review refer to the adminis-
majority of pharmacological activity. S-(+)- tration of the racemate.
ibuprofen has been reported to be about 160 times
more potent than R-(–)-ibuprofen in inhibiting 1. Analytical Methods
prostaglandin synthesis in vitro.[2-4] Racemic Several analytical methods are available for
ibuprofen has half the potency of S-(+)-ibuprofen quantitative analysis of ibuprofen in biological
in inhibiting platelet aggregation and thromboxane specimens (table I). The earlier methods employed
formation, while R-(–)-ibuprofen was about 2 or- thin-layer spectrophotometric, colorimetric, paper
ders of magnitude less active.[5] Ex vivo studies of chromatography, differential pulse polagraphy,
thromboxane generation in clotting blood also gas-liquid chromatography or direct liquid intro-
found S-(+)-ibuprofen to be twice as potent as the duction mass spectrometry (MS).[16-21,33,37,40,78,79]
racemate.[6] However, due to greater precision and facile sam-
In the treatment of rheumatoid arthritis, osteo- ple preparation, these methods have largely been
arthritis, ankylosing spondylitis, acute gouty ar- replaced by high performance liquid chromatogra-
thritis and dysmenorrhoea, therapeutic doses of phy (HPLC) [see table I], gas chromatography
ibuprofen have proven to be equiefficacious as (GC),[22,25,26,45,80] gas chromatography-mass spec-
compared with other commonly used NSAIDs. trometry (GC-MS)[52,70,72,74,77,81,90,97,105,106] and a
Gastrointestinal (GI) complications are the most recent report describes the use of high performance
common adverse effect, but renal dysfunction may thin-layer chromatography.[107]
also occur.[7,8] The earlier assays of ibuprofen overlooked the
Excellent review articles describing the clinical fact that it is administered as the racemate. How-
pharmacokinetics and pharmacodynamics of sev- ever, since 1975 GC and HPLC techniques have
eral other chiral NSAIDs are available.[9-15] Similar been available which allow for the separation and
to other NSAIDs, ibuprofen exhibits enantio- quantification of the 2 enantiomers. These methods
selectivity in action and disposition. As with all of stereospecific analysis of ibuprofen have been
© Adis International Limited. All rights reserved. Clin Pharmacokinet 1998 Feb; 34 (2)
Ibuprofen: The First 30 Years 103
Table I. Chromatographic assays for ibuprofen

MQC (mg/L) Volume (ml) Technique Specimen Reference
Nonstereospecific assays
0.5 1.0 GLC Plasma 16
2.0 1.0 Colorimetric Dog plasma/urine 17
0.5 1.0 GLC Serum 18
1.0 0.1 GLC Serum 21
0.4 1.0 GC Plasma 22
5.0 0.1 HPLC Plasma 23
0.5 1.0 HPLC Dog plasma 24
1.0 1.0 GC Plasma/urine 25
0.5 0.2 GC-MS Serum/synovial fluid 26
0.1 0.5 HPLC Rabbit plasma 27
0.5 1.0 HPLC Serum 28
1.0 1.0 HPLC Plasma/urine 31
1.0 2.0 GC Haemolysed blood 33
1.25 1.0 GC Plasma 34
0.25 NR HPLC Plasma 36
5.0 1.0 GC Plasma 37
1.0 5.0 GC Serum 40
NR 1.0 HPLC Plasma 42
0.5 0.25 HPLC Plasma/serum 44
0.02 1.0 GC Urine 45
5.0 0.5 HPLC Whole blood/ serum 46
0.5 0.1/0.01 HPLC Plasma/urine 50
1.0 1.0 GC-MS Dog serum 52
0.05 1.0 HPLC Whole blood 54
2.5 1.0 HPLC Urine 56
0.1 0.5 HPLC Plasma/tissue 58
0.25/0.05 0.1 HPLC Human/rat plasma 60
0.001 0.5 HPLC Plasma/synovial fluid 63
Continued over page
104 Davies
Table I. Contd
MQC (mg/L) Volume (ml) Technique Specimen Reference
0.05 1.0 HPLC Rat plasma/urine 64
0.0005 1.0 HPLC Serum 68
25.0 1.0/2.0g GC-MS Whole blood/tissue 70
NR 0.2 GC-MS Serum 72
0.014 0.5 HPLC Saliva 73
NR 1.0 GC-MS Serum/saliva/urine 74
10.0 0.05 GC-MS Serum 76
0.05 1.0 HPTLC Plasma 77
0.05 1.0 HPLC Urine 34
a
Stereospecific assays
NR NR GC-MS Urine 26
1.0 1.0 GLC Plasma/urine 78
10.0 9.0 LC-MS Equine urine 79
0.25 1.0 GC Plasma 80
0.1 NR GC-MS Plasma/urine 81
0.1 0.5/0.1/0.1 HPLC Plasma/urine/bile 86
0.017 NR HPLC Plasma 87
0.003 0.2 GC-MS Plasma/synovial fluid 90
0.1 1.0 HPLC Plasma /urine 94
0.4 0.1 HPLC Rat plasma 95
0.005 0.1 GC-MS Plasma 97
0.37/0.17 R 0.5 HPLC Plasma 99
0.05 NR GC-MS Plasma 101
0.4 NR HPLC Rat plasma 102
a MQC for each enantiomer.
Abbreviations: GC = gas chromatography; GC-MS = gas chromatography-mass spectrometry; GLC = gas-liquid chromatography; HPLC =
high performance liquid chromatography; HPTLC = high performance thin-layer chromatography; LC-MS = liquid chromatography-mass
spectrometry; MQC = reported minimum quantifiable concentration; NR = not reported.
recently reviewed,[108] and involve formation of produced peak plasma drug concentrations (Cmax)
amide or ester diastereomeric derivatives through significantly earlier and higher than ibuprofen acid
the use of an optically pure derivatising reagent or granules, postulated to be because of the faster
and separate chromatographic quantification on an dissolution of ibuprofen lysinate.[170,220] Ibuprofen
achiral stationary phase. Stereospecific chromato- lysine salt has an absolute bioavailability ap-
graphy analysis can also be accomplished though proaching 100%.[88]
the transient formation of diastereoisomers and A study of the influence of absorption rate and
quantification on a chiral stationary phase. More dosage size demonstrates solutions are absorbed
recently, stereospecific and nonstereospecific more quickly [time to reach peak plasma drug
analysis has been accomplished using micellar concentrations (tmax) < 0.25 hours] than the tablet
electrokinetic capillary chromatography, capillary (tmax ≈ 2 hours).[197] The rate and extent of ibu-
zone electrophoresis and supercritical fluid chro- profen absorption from suspensions were signifi-
matography, but complete assay validation and cantly less than that of tablets.[154] A liquid formu-
application to pharmacokinetic studies remains lation prepared from effervescent tablets had a
limited.[76,101,109-112] In addition, stereospecific slower absorption than expected, probably due to
resolution of racemic ibuprofen using L-arginine incomplete dissolution.[162] The pH regulators
impregnated thin-layer chromatography (TLC) (aluminum hydroxide, calcium carbonate, tartaric
and by HPLC with peroxylate chemiluminescence acid and sodium bicarbonate) were formulated as
detection has been accomplished.[113,114] additives in ibuprofen hard gelatin capsules. A for-
mulation of ibuprofen with sodium bicarbonate
2. Pharmacokinetic Properties was found to have significantly faster absorption
(a tmax of 0.4 hours) than aluminum hydroxide cap-
2.1 Oral Absorption sules (tmax = 3.1 hours). The corresponding tmax for
calcium carbonate and tartaric acid capsules were
Ibuprofen is most often administered orally, but
it has also been administered topically, intra- 1.7 and 2.0 hours, respectively. A rank order of
ocularly, intravenously, intramuscularly and rec- correlation existed between dissolution parameters
tally. Conventional rapid release tablets and a sus- and the rate of absorption (tmax, Cmax, mean resi-
tained release preparation are commercially dence time and lag time). No differences were
available. noted in the area under the concentration-time
Table II shows the absorption properties of curve (AUC) values.[155]
ibuprofen when administered by different routes The bioavailability of rectally administered so-
and formulations. Following administration of sin- dium ibuprofen solution and aluminum ibuprofen
gle doses of regular release preparations, ibuprofen suspension indicate that the suspension was less
is rapidly absorbed, with peak plasma or serum bioavailable than the solution irrespective of the
drug concentrations observed within 3 hours post- route of administration. The mean AUC and Cmax
drug administration (refer to table II). Different from rectal administration were 87% and 62% of
brands of ibuprofen may not be pharmacokinetic- the corresponding values achieved after oral ad-
ally interchangeable and differences in rate and ministration. In addition, the tmax were 1 to 3 hours
the extent of absorption between formulations longer with the rectal solution, indicating a slower
have been determined (refer to table II). A soluble rate of absorption.[155]
granular form of ibuprofen and L-arginine demon- When administered with food, the tmax was
strates quicker absorption and a significantly ≈20% lower and was attained more slowly (after
higher plasma concentrations in the first hour com- 1.5 to 3 hours).[8,86,221] A more recent stereo-
pared with tablet preparations.[166,213] Ibuprofen specific study demonstrated that food did not have
administered as a lysine salt to healthy volunteers a significant effect on ibuprofen enantiomer
106 Davies
Table II. Absorption characteristics of ibuprofen (oral dosage formulations administered in single doses except where indicated)
n (patient type) Agea (y) [range] Dose [no. of days] Cmax tmax AUC Reference
(mg/L)b (h)b (mg/L • h)
Nonstereoselective studies
2 NR Ibuprofen 200 tid for 14 days – day 1 22 1.5 NR 115
Ibuprofen 200 tid for 14 days – day 14 19 1.5 NR
20 [22-50 Ibuprofen 200 21.8 1.0 NR 16
5 NR Ibuprofen 400 27.92 1.1 NR 116
4 (with arthritis) NR Ibuprofen 400 30.15 1.165 NR
32 (from 62 children with 8.8 [1.5-16] Ibuprofen 20 mg/kg tid 100 1-2 NR 117
JRA)
8 (from 62 children with JRA) Ibuprofen 30 mg/kg tid 130 1-2 NR
22 (from 62 children with Ibuprofen 40 mg/kg tid 150 1-2 NR
JRA)
17 children JRA 11 Ibuprofen 40 mg/kg 31.0 1-2 NR 118
6 [24-25] Ibuprofen 300 SC tablets tid for 14 119
days – day 1
First Admin 11.5 2.0 NR
Second Admin 12.3 2.0 NR
Ibuprofen 300 SC tablets tid for 14
days – day 7
Ibuprofen 300 SC tablets tid for 14
days – day 14
6 [24-48] Ibuprofen guaiacol-ester 300 SC 6.3 4.0 49.6 120
tablets
5 [35-45] Ibuprofen 300 guaiacol-ester 300 4.7 2.0 46.8
syrup
Ibuprofen 200 SC tablet 7.3 2.0 48.8
18 [28-35] Study I – Ibuprofen 300 capsule 21.1 2.17 91.5 121
20 (Amersol®)
[20-33] Ibuprofen 300 tablet (Motrin®) 32.4 1.32 89.9
Ibuprofen 300 solution
Study II – Ibuprofen 400 capsule 31.9 0.46 88.5
(Amersol®)
Ibuprofen 200 capsule (Amersol®) 31.4 2.00 116
Ibuprofen 400 tablet (Motrin®) 39.0 1.25 119
Ibuprofen 300 solution 37.9 1.39 112
45.5 0.53 110
8 [19-35] Ibuprofen 400 23.6 2.0 NR 122
Ibuprofen 400 (Dolgit®) 26.8 2.0 NR
8 RA NR Ibuprofen 400 qid – dose 1 27.6 1.17 319.8 123
Ibuprofen 400 qid – day 7 28.7 1.11 321.06
Ibuprofen 400 qid – day 14 28.8 1.03 289.5
9 FHF (of 15 ALD) 54.3 Ibuprofen 400 22.0 1.5 79.2 124
6 PHF (of 15 ALD) 53.0 Ibuprofen 400 21.1 2.6 100.0
29 Ibuprofen 400 27.9 1.9 103.0
15 25 [22-35] Ibuprofen 400 tablets 37.7 1.3 122 125
Ibuprofen 2 × 400 tablets 61.1 1.6 206
Table II. Contd

Ibuprofen 3 × 400 tablets 87.7 1.7 286
Ibuprofen 400 solution 43.8 0.71 121
15 [18-41] Source A – Ibuprofen 200 27.0 1.375 76.0 126
Source A – Ibuprofen 300 20.1 1.695 93.6
Source A – Ibuprofen 400 25.6 2.48 113.6
Source B – Ibuprofen 200 19.0 1.95 63.0
Source B – Ibuprofen 400 36.4 2.07 128.8
20 28 [19-42] Ibuprofen 400 Q6H for 8 doses 40.5 1.4 115 127
Ibuprofen 400 and paracetamol 650 42.3 1.4 114
Q6H for 8 doses
10 [24-51] Ibuprofen 400 (Dolgit® retard) 26.4 4.0 NR 128
4 39.5 [31-47] Ibuprofen 400 33.7 C 3.0 C 144 C 38
32.1 V 3.0 V 137 V
17 70 [65-78] Ibuprofen 400 32.5 1.0 NR 139
Ibuprofen 800 60.2 1.5 NR
Ibuprofen 1200 71.1 1.5 NR
10 24 [22-27] Ibuprofen 600 56.6 1.5 217 130
Ibuprofen 600 + 1 g sucralfate qid the 51.9 1.72 191
day before the study and 1g on the
morning of the study
37 [20-88] 131
7 Young male 34.3 Ibuprofen 600mg 45.4 0.93 NR
10 Young female 26.6 Ibuprofen 600mg 51.8 1.95 NR
11 Elderly male 67.1 Ibuprofen 600mg 42.4 1.52 NR
9 Elderly female 71.0 Ibuprofen 600mg 53.3 1.97 NR
11 Obese 35 Ibuprofen 600mg 36.9 1.39 NR 132
11 36 Ibuprofen 600mg 47.7 1.25 NR
8 23 [17-32] Ibuprofen 600mg resinated granules 32.76 1.375 119.60 133
Ibuprofen 600mg micro-incapsulated 29.54 2.0625 102.00
granules
13 [23-31] Ibuprofen 400mg 56 1.38 203 134
Ibuprofen 400mg + cimetidine tid 64 1.33 216
400mg 48h before ibuprofen and
continuing during study
Ibuprofen 400mg + Ranitidine 150mg 57 1.23 196
bid 48h before ibuprofen and
8 CRI [20-48] Ibuprofen 600mg 32.2 2.8 NR 134
10 [21-47] Ibuprofen 600mg 49.1 1.2 NR
11 [22-35] A 282 39.0 1.82 167 135
B 386 34.1 2.48 164.7
C 384 38.8 2.48 167.7
12 35 [25-40] Ibuprofen 400mg 32.3 1.5 113.2 136
Sucralfate 1g 2 days prior qid and 26.2 2.2 107.1
Ibuprofen 400mg with 1g Sucralfate
and 2 addtional 1g tablets during the
study
7 51.86 [37-66] Ibuprofen 400mg × 2 tablets tid for 15 41.14 1.29 NR 137
days
6 23.6 [18-33] Ibuprofen 300mg SC tablets 16.3 1.79 59.24 138
Continued over page
108 Davies
Table II. Contd

Ibuprofen 300mg granules 17.6 1.58 51.39
Ibuprofen 400mg SC tablets 21.7 2.71 64.89
Ibuprofen 600mg coated tablets 33.2 1.95 105.05
8 RA 54.125 [26-67] Ibuprofen 600mg tid × 2 days and 7am 44.1 1.2 NR 139
day 3 – day 1
Ibuprofen 600mg tid × 2 days and 7am 45.9 1.3 NR
day 3 – day 3
18 [19-41] Inza® 200mg × 4 tablets 42.4 2.9 196 140
Inza® 400mg × 2 tablets 41.9 3.0 191
Brufen® 200mg × 4 tablets 59.6 1.8 197
12 [20-53] Ibuprofen 300mg × 2 SR tablets 25.1 5.3 144.0 141
Ibuprofen 400mg × 2 SR 31.3 3.0 274.1
Ibuprofen 400mg × 2 FCT 68.5 2.0 99.3
8 [20-30] Ibuprofen 400mg 35.3 1.28 127.53 142
Ibuprofen 400mg with concurrent 41.00 1.00 122.61
antacid suspension (62ml) Al+
Mg(OH)2
Ibuprofen 400mg with antacid 40.66 1.03 117.86
suspension administered 1h after
ibuprofen
Ibuprofen 400mg with concurrent 37.33 0.95 113.97
antacid suspension and then 3 more
doses of antacid given every 5h
6 NR 1: Ibuprofen 200mg 14.94 2.605 58.37 143
4: Ibuprofen 200mg 20.96 1.737 78.41
12 NR 2: Ibuprofen 200mg 25.79 1.694 106.2
4: Ibuprofen 200mg 24.46 1.858 106.2
12 NR 3: Ibuprofen 200mg 23.24 2.028 122.8
4: Ibuprofen 200mg 23.43 2.126 109.8
8 NR Ibuprofen 800mg SR 16.8 7.5 180.2 144
Fasted
12 [21-35] Ibuprofen SR 800mg tablet fasting 13.8 11.6 81.3 145
Ibuprofen SR 800mg tablet following 12.7 12.6 89.1
ranitidine 300mg
Ibuprofen 2 × 400mg tablets fasting 47.3 1.86 195
6 [20-25] Ibuprofen 400mg NR NR 116 146
Nizatidine 300mg nightly for 6 days + NR NR 121
ibuprofen 400mg on day 3
Cimetidine 800mg nightly for 6 days + NR NR 109
ibuprofen 400mg on day 3
17 [18-24] Brufen® 600mg 57.8 1.4 217.1 147
Burana® 600mg 44.9 2.1 221.3
Ibumetin® 600mg 54.3 1.6 198.7
8 28 [25-37] Ibuprofen 800mg + 120ml water 55.6 1.59 217.78 148
Ibuprofen 800mg dissolved in 40.9 2.44 180.26
Coca-Cola®
Table II. Contd

Ibuprofen 800mg dissolved in orange 49.4 1.41 195.58
juice
Ibuprofen 800mg dissolved in diluted 48.4 2.56 203.51
cherry syrup
12 25 Phase I – ibuprofen 600mg qid × 3 63.36 1.65 166.71 149
[18-55] days - day 4 ibuprofen 600mg in the
morning
Phase II – ibuprofen 600mg qid and 71.34 1.08 175.36
ranitidine Hcl 300mg × 3 days with
breakfast – day 4 300mg Rantidine 2h
before ibuprofen 600mg
Phase III – ibuprofen 600mg qid and 66.76 1.27 200.25
ranitidine HCl 300mg × 3 days with
breakfast – day 4 cimetidine 800mg
2h before Ibuprofen 600mg
8 24 Sodium ibuprofen 800mg solution 80.7 0.33 200.3 150
orally
Aluminum ibuprofen 800mg 28.7 2.12 179.1
Suspension orally
Sodium ibuprofen 800mg solution 50.3 1.14 175.5
rectally
Aluminum ibuprofen 800mg 19.2 2.44 102.9
suspension rectally
8 27 [25-39] 1000mg Imbun® fasted 69.1 0.55 174.3 86
600mg Dolgit® fasted 50.8 0.89 205.5
1000mg Imbun® fed 50.3 1.18 169.7
600mg Dolgit® fed 44.6 1.55 169.0
13 [65-80] Ibuprofen 600mg 24.25 1.6 101.48 151
5 (of 11) [19-21] Ibuprofen 800mg SR light breakfast 16.2 7.6 NR 152
6 (of 11) Ibuprofen 800mg SR fasted 18.4 5.33 NR
6 (of 11) Ibuprofen 800mg SR heavy breakfast 27.9 13.2 NR
5 (out of 8) [20-27] Ibuprofen 800mg SR fed – retained in 22.4 6.8 213.8 153
stomach
3 (out of 8) Ibuprofen 800mg SR fed – ejected 18.5 6 174.3
from stomach
10 (of 35) 31.2 [19-30] Ibuprofen 800mg tablets tid × 7 days – 61 1.6 98 154
day 1
10 (of 35) Ibuprofen 800mg tablets tid × 7 days– 66 1.0 123
day 4
10 (of 35) Ibuprofen 800mg tablets tid × 7 days– 52 1.9 241
day 8
Ibuprofen 800mg aqueous suspension 47 1.7 78
tid × 7 days – day 1
Ibuprofen 800mg orange juice 42 1.6 77
suspension tid × 7 days – day 1
Continued over page
110 Davies
Table II. Contd

10 24 Ibuprofen aluminum hydroxide 25.6 3.1 148 155
capsules
Ibuprofen sodium bicarbonate 51.4 0.4 137
capsules
Ibuprofen calcium carbonate capsules 32.2 1.7 150
Ibuprofen tartaric acid capsules 30.8 2.0 158
10 23.3 [20-26] 400mg Iburo® 30.0 1.6 NR 156
400mg Burana® 23.2 2.3 NR
28 49 [19-60] Ibuprofen 800mg SR × 2 × 14 days – 26.2 6.0 402.0 157
day 1
Ibuprofen 800mg SR × 2 × 14 days – 22.9 6.0 377.0
day 15
30 71 [65-85] Ibuprofen 800mg SR × 2 × 14 days – 24.6 6.0 387.0
day 1
Ibuprofen 800mg SR × 2 × 14 days – 26.6 6.0 382.8
day 15
16 28.9 Ibuprofen 600mg SC tablets 52.03 1.05 190.76 158
Ibuprofen 600mg FCT 40.33 1.54 183.55
8 29.8 Ibuprofen 200mg slow IV 40.4 0.018 227.16 87
Ibuprofen 400mg slow IV 83.0 0.018 435.6
Ibuprofen lysine 500mg 31 0.75 305.58
13 CF [6-11] Ibuprofen 300mg 38 1.13 96.7 159
4 Ibuprofen 400mg 29 2.13 105.0
13 CF Ibuprofen 600mg 65 1.82 180.0
4 Ibuprofen 13.4 mg/kg 48 1.1 101.67
[8-11] Ibuprofen 13.29 mg/kg 66 1.0 188.33
9 (of 17 paediatric patients 6.7 [3.1-9.6] Ibuprofen 5mg/kg 28.4 1.1 NR 160
with fever)
8 (of 17 paediatric patients 6.2 [3.1-9.6] Ibuprofen 10 mg/kg 43.6 1.2 NR
with fever)
6 33 Ibuprofen 400mg 32.4 1.5 173 161
Ibuprofen 400mg and 850mg Mg(OH)2 25.5 0.9 179
14 23.14 [21-25] Ibuprofen 400mg FCT 38.8 1.78 155.8 162
Ibuprofen 400mg SGC 63.1 0.55 146.4
Ibuprofen 400mg EFT 31.7 1.91 137.7
6 21.3 [21-23] Ibuprofen 800mg 54.7 (1.7 1.67 (5) 214.3 (10.5) 163
CM) mg/kg mg/kg × h
12 23 [18-40] Ibuprofen 600mg 64.5 1.15 190.83 164
Ibuprofen 600mg and misoprostol 66.97 1.42 200.42
200μg
Ibuprofen 600mg and ranitidine HCl 61.63 0.93 182.45
38 (febrile children) [0.25-12] Ibuprofen 5 mg/kg 19.03 1.60 71.12 165
46 (febrile children) Ibuprofen 10 mg/kg 34.35 1.54 115.76
8 37.2 Ibuprofen 200mg sachets 26.1 0.28 240.84 166
Ibuprofen 200mg tablets 16.3 1.5 246.78
Ibuprofen 400mg sachets 56.4 0.41 430.02
8 32.1 Ibuprofen 400mg tablets 43.0 1.06 429.66
Table II. Contd

22 NR Ibuprofen 200mg capsule 19.6 1.59 60.3 167
Ibuprofen 200mg tablet Nuprin® 19.2 1.06 58.8
49 Febrile children [0.25-12] Ibuprofen 8 mg/kg 35.8 0.7 102.6 168
18 Febrile children 5.8 Ibuprofen 6 mg/kg 26.67 0.90 NR 169
12 24.0 [20-30] Ibuprofen 600mg lysine sachets 59.54 0.45 150.1 170
10 Haemophiliacs 33 Ibuprofen 400mg acute 18.49 1.0 NR 171
Ibuprofen 400mg Q6H for 2 21.72 2.0 NR
weeks
5 Controls 29 Ibuprofen 400mg 27.73 1.0 NR
5 Group I (10 patients with 20 Enteral feeding 44.2 0.4 62.2 172
burn)
5 Group II (10 patients with 38 Hospital diet 12.4 2.5 42.9
burns)
6 [20-48] Ibuprofen 200mg topical 1.4 4.83 12.48 173
Ibuprofen 200mg topical 0.28 7.0 1.35
Ibuprofen 200mg topical 0.39 6.8 3.19
6 35.3 [29-39] Ibuprofen 400mg 24.48 1.25 83.59 174
Ibuprofen 400mg and colestipol 21.18 1.42 82.60
HCl 10g
Ibuprofen 400mg and CSM 8g 16.07 2.25 61.89
24 [18-50] I400 30.6 1.81 102.1 175
IC301 33.2 1.38 100.2
IC302 26.4 1.89 105
IC601 34.9 1.09 104.2
IC602 29.8 1.89 98.0
11 Infants [0.5-1.5] Ibuprofen 7.6 mg/kg 24.4 2.93 78.1 176
20 CF 11.5 [1-42] Ibuprofen 25.8 mg/kg tablets 77.1 1.56 210 75
16 Ibuprofen 25.3 mg/kg elixir 101.7 0.5 191.7
18 30.2 [22-41] Profinal® 600mg 54.9 2.08 234.7 177
Brufen® 600mg 53.7 1.92 222.5
18 26.3 [20-38] Ibuprofen 500mg topically 7.1 2.4 31 178
Ibuprofen 400mg tablet 26.7 1.1 114
9 26.7 Ibuprofen 800mg rapid release 45.23 2.56 213.66 179
Ibuprofen 800mg SR 25.7 5.56 206.38
Ibuprofen 800mg EC supension 54.28 1.89 205.82
6 [21-37] Ibuprofen 300mg suspension 31.98 1.17 98.16 180
Ibuprofen 300mg matrix with xanthum 9.67 2.67 78.92
gum tablet
Ibuprofen 300mg matrix xanthum 9.97 3.40 71.40
gum/CL490
18 NR Ibuprofen 800mg SR fasting 18.07 9.28 268.79 181
Ibuprofen 800mg SR with food 20.93 8.67 271.96
18 NR Ibuprofen 400mg 42.28 0.93 120.08 182
Ibuprofen 400mg 42.55 0.97 118.32
21 PINB GA 26.8 Ibuprofen lysinate IV 10 mg/kg 180.6 1.0 769.8 183
[22-31 weeks]
18 Dental 28.4 Ibuprofen 400mg 44.7 0.53 100.87 184
Continued over page
112 Davies
Table II. Contd

Stereospecific studies
4 [31-45] S-Ibuprofen 400mg solution NR 0.25-0.5 93.1 S 185
NR 0.25-0.5 101 R
R-Ibuprofen 400mg solution NR 0.25-0.5 59.3 S
NR 0.25-0.5 82.3 R
Racemic ibuprofen 800mg solution NR 0.25-0.5 128.3 S
2 NR Ibuprofen 200mg 11.55 S 1.5 S 128.85 S 82
8.55 R 1.5 R 76.25 R
12 [18-34] Ibuprofen 400mg tablet 7.7 R 4.4 R 42 R 186
Apotex 8.7 S 6.0 S 58 S
Ibuprofen 400mg 18.0 S 1.2 S 50 R
Motrin® 17.1 S 1.3 S 58 S
8 RA 58.38 [28-61] Ibuprofen 800mg 9.32 R 2.0 R NR 187
12.0 S 2.6 S NR
14 [19-37] Motrin FC 600mg 30.04 S 1.44 106.87 S 188
27.45 R 74.21 R
8 Apo-ibuprofen FC 600mg 31.50 S 2.75 121.72 S
23.54 R 73.87 R
8 Motrin SC 300mg 23.90 S 1.42 90.77 S
20.34 R 56.86 R
6 Apo-ibuprofen SC 300mg 26.71 S 2.83 100.18 S
17.32 R 51.51 R
6 [21-42] Ibuprofen 800mg 27.2 R 1.4 2 R 75.23 R 189
28.5 S 1.625 S 107.67 S
Ibuprofen 800mg 2nd day of 3 days of 27.1 R 1.833 R 77.75 R
cimetidine 1g 29.6 S 2.3 S 114.77 S
4 26.75 [22-36] R-Ibuprofen 300mg + R-[2H3] 27.6 R 0.458 R 68 R 190
4.80 S 1.5 S 25.29 S
Ibuprofen 304mg solution 27.8 0.415 68 R-[2H3]
R-[2H3] R-[2H3]
5.15 S 1.5 S 27.5 S-[2H3]
[2H3] [2H3]
8 [25-47] S-ibuprofen 300mg 18.7 S 1.4 S 67.2 S 3
19.8 R 1.0 R 57.2 R
R-ibuprofen 300mg 6.4 S 2.1 S 32.4 S
14.8 R 1.7 R 57.0 R
Racemic ibuprofen 600mg 16.8 S 1.9 S 89.8 S
6 [25-38] Ibuprofen 600mg 26.7 R 1.46 R 67.4 R 191
Cimetidine 400mg bid for 3 days 25.0 S 1.46 S 89.7 S
then ibuprofen 600mg + cimetidine 37.3 R 1.17 R 92.5 R
400mg bid 32.5 S 1.38 S 106.7 S
24 22.6 [21-25] Ibuprofen 400mg 12.2 R 1.4 R 35.8 R 192
17.1 S 1.49 S 64.0 S
3 Ibuprofen 200mg 6.9 R 1.33 R 21.3 R
9.33 S 1.33 S 36.6 S
6 Ibuprofen 400mg 12.8 R 1.42 R 39.0 R
18.82 S 1.42 S 70.98 S
3 Ibuprofen 800mg 24.63 R 1.33 R 71.67 R
Table II. Contd

36.6 S 1.5 S 140.6 S
4 [23-28] Ibuprofen 200mg 10.0 R 1.13 R 85.98 R 193
14.1 S 1.13 S 157.2 S
Ibuprofen 400mg 14.1 R 1.38 R 150.6 R
16.9 S 1.87 S 271.44 S
Ibuprofen 800mg 24.4 R 1.57 R 264.84R
31.6 S 1.89 S 507.48 S
Ibuprofen 1200mg 29.5 R 1.81 R 309.9 R
47.7 S 2.19 S 775.8 S
11 [25-47] Study I: S-Ibuprofen 300mg 19.05 S 1.44 S 65.7 S 194
Study I: R-Ibuprofen 300mg 21.6 R 1.07 R 55.7 R
Study I: Ibuprofen 600mg racemate 6.51 S 2.08 S 34.4 S
14.3 R 1.53 R 14.3 R
1 Study II: S-Ibuprofen 150mg 16.4 S 1.80 S 16.4 S
9.14 S 1.35 S 39.2 S
Study II: S-Ibuprofen 500mg 27.3 S 1.97 S 116.6 S
8 patients with arthritis 49.75 [28-55] Ibuprofen 800mg Q8H for 3 days 24 R 1.1 R 67 R 195
26 S 1.3 S 93 S
16 NR S-Ibuprofen 130mg 9.36 S 1.10 S 29.58 S 196
R-Ibuprofen 130mg 8.35 R 1.0 24.7 R
2.08 S 3.0 12.1 S
Racemic ibuprofen 200mg 7.14 R 1.31 R 22.3 R
7.98 S 2.49 S 38.7 S
6 [32-44] Ibuprofen 50mg solution NR <0.25 6.37 R 197
NR <0.25 7.52 S
Ibuprofen 100mg solution NR <0.25 11.5 R
NR <0.25 13.3 S
NR <0.25 23.5 S
NR <0.25 42.6 S
NR <0.25 70.6 S
NR <0.25 126.1 S
Ibuprofen 600mg tablet NR 2.17 52.7 R
NR 2.17 70.8 S
18 Febrile children 5.8 Ibuprofen 6 mg/kg 13.39 R 0.733 R NR 169
13.86 S 1.11 S NR
11 NR Ibuprofen 600mg fasted 25 R 1.2 R 74 R 198
38 S 1.3 S 127 S
Ibuprofen 600mg fed 16 R 1.5 R 73 R
22 S 2.1 S 118 S
Sucralfate 1g qid × 2 Days then 19 R 1.5 R 59 R
Ibuprofen 600mg 29 S 1.6 S 116 S
12 23.6 [19-27] Ibuprofen 600mg 14.0 R 1.7 R 50.5 R 199
16.2 S 2.1 S 78.9 S
Ibuprofen 400mg Q8H for 5 days 10.6 R 1.6 R 31.1 R
Continued over page
114 Davies
Table II. Contd

14.3 S 2.3 S 48.0 S
39 Knee OA (of 45 in study) 58 [31-87] Ibuprofen 300mg qid × 4 days 12.0 R 1.7 R 35.9 R 200
12.7 S 2.1 S 54.4 S
6 Hip OA (of 45 in study) Ibuprofen 600mg qid × 4 days 18.7 R 1.6 R 55.5 R
18.2 S 2.0 S 81.4 S
Ibuprofen 300mg 10.5 R 1.9 R 27.7 R
11.1 S 2.0 S 42.9 S
15 Ibuprofen 600mg 16.4 R 2.3 R 56.6 R
13.8 S 1.9 S 74.3 S
10 [19-30] Ibuprofen 400mg orally + 10mg 17.39 R 1.45 R 226.2 R 201
S-d4-ibuprofen 19.15 S 1.5 S 253.2 S
8.4 S-d4
Ibuprofen 400mg + 10mg 22.39 R NR 243.6 R
S-d4-ibuprofen IV 24.61 S NR 258.0 S
8.4 S-d4
50 RA group I 25 60 S-Ibuprofen 400mg tid × 14 days 21.8 S 2.3 S 77.3 S 202
50 RA group II 25 56 Racemic ibuprofen 600mg tid × 14 17.7 R 2.3 R 67.6 R
days
20.3 S 2.4 S 86.2 S
8 patients with cirrhosis 56.25 [42-68] Ibuprofen 600mg 23.4 R 1.8 R 73.5 R 203
8 patients with cirrhosis 51.63 [41-62] S-Ibuprofen 400mg 23.3 S 1.8 S 94.5 S
26.8 S 1.8 101
8 52 [46-59] Ibuprofen 600mg 19.5 R 1.2 R 87.1 R
8 50 [46-61] S-Ibuprofen 400mg 14.2 S 1.1 S 81.6 S
24.9 S 2.1 S 144 S
5 25 [21-39] Ibuprofen 1200mg 25.4 R 1.8 R 106 R 204
35.4 S 1.8 S 186 S
10 patients with renal failure 60.2 Ibuprofen 800mg NR NR 397.0 R 205
NR NR 815.5 S
11 UDS 62.2 Ibuprofen 800mg NR NR 328.4 R
NR NR 474.2 S
10 Controls 57.9 Ibuprofen 800mg NR NR 239.7 R
NR NR 286.8 S
11 Infants [0.5-1.5] Ibuprofen 7.6 mg/kg 11.8 R 2.93 R 36.6 R 176
9.7 S 2.93 S 31.5 S
12 23 [20-29] R-Ibuprofen 300mg solution 34.9 R 0.44 R 350.82R 206
7.63 S 1.375 S 175.20 S
S-Ibuprofen 300mg solution 29.7 S 0.49 S 69.22 S
R-Ibuprofen 300mg + 300mg 29.6 R 0.55 R 283.56R
S-ibuprofen solution 29.0 S 0.63 S 355.08 S
R-Ibuprofen 300mg + S-Ibuprofen 30.0 R 0.48 R 270.09R
600mg solution 49.8 S 0.53 S 534.84 S
46 [25-88] Ibuprofen 400mg × 2 tablets 20.7 R 1.5 R 65.47 R 207
NRCP 26.1 S 1.5 S 85.55 S
9 Young patients 29.2 [20-34] Ibuprofen 800mg NR NR 135.6 R 208
NR NR 160.7 S
9 Elderly patients 55.4 [44-63] Ibuprofen 800mg NR NR 216.0 R
NR NR 312.6 S
Table II. Contd

10 59.9 Ibuprofen 800mg NR NR 239.5 R 209
286.8 S
32 DM 62.6 Ibuprofen 800mg NR NR 338.1 R
715.8 S
HT Ibuprofen 800mg NR NR 396.3 R
800.6 S
HL Ibuprofen 800mg NR NR 374.9 R
780.5 S
HU Ibuprofen 800mg NR NR 490.1 R
433.5 S
CAD Ibuprofen 800mg NR NR 377.6 R
796.1 S
CVD Ibuprofen 800mg NR NR 212.4 R
320.4 S
CHF Ibuprofen 800mg NR NR 423.0 R
529.1 S
CRF Ibuprofen 800mg NR NR 436.1 R
768.3 S
14 [23-33] S-Ibuprofen 400mg tablet NR NR 87.7 99
S-Ibuprofen 400mg solution NR NR 82.2
Racemic Ibuprofen 400mg 18.4 R 1.09 R 48.1 R
18.6 S 1.16 S 63.5 S
S-Ibuprofen 200mg 13.2 S 1.75 S 47.4 S
18 [21-36] Racemic 800mg 25.3 R 1.61 R 74.4 R
28.0 S 1.80 S 113.2 S
Racemic Ibuprofen 1200mg 36.5 R 1.43 R 104.6 R
43.2 S 1.75 S 169.7 S
8 Female 24 R-ibuprofen 6 mg/kg 36.9 0.7 97.3 210
8 Female OCS 22 35.9 0.6 92.8
8 Male 21 33.8 0.5 97.4
19 22.5 Ibuprofen 200mg 7.5 S 2.21 NR 211
20 dental patients 22.9 Ibuprofen 200mg and Misoprostol 6.1 S 2.75 NR
200μg
18 27.4 [24-36] Ibuprofen 400mg fasting 21.34 R 1.25 R 49.82 R 212
19.13 S 1.25 S 67.59 S
Ibuprofen 400mg postprandial 11.10 R 2.58 R 38.93 R
14.35 S 2.94 S 67.59 S
7 25.6 Brufen®: 400mg S-(+)-ibuprofen 36.2 0.48 86.4 213
arginine in 150ml H20
Burana®: 400mg R-(–)-ibuprofen 35.3 R 0.83 R 104.7 R
arginine in 150ml H20 9.7 S 1.5 R 47 S
Ibemetin®: 400mg (+/–)-ibuprofen 25.6 R 0.38 R 65.3 R
arginine in 300ml H20 29.9 S 0.51 S 105.1 S
20 27.6 [23-34] Ibuprofen 400mg tablets 17.19 R 1.5 R NR 214
15.51 S 1.5 S NR
Ibuprofen 800mg tablets 30.12 R 1.0 R NR
Continued over page
116 Davies
Table II. Contd

28.01 S 1.0 S NR
Ibuprofen 400mg effervescent 25.33 R 0.125 R NR
22.11 S 0.125 S NR
Ibuprofen 800mg effervescent 40.56 R 0.125 R NR
36.69 S 0.75 S NR
6 NR Ibuprofen 400mg tablets 17.8 R 1.59 R 52.2 R 215
19.0 S 1.64 S 75.0 S
a Mean age; range in parentheses.
b Values are for racemate, unless otherwise indicated.
Abbreviations: ALD = alchoholic liver disease; AUC = area under the concentration-time curve; C = capillary plasma; CAD = cornary artery
disese; CF = cystic fibrosis; CHF = congestive heart falure; CL490 = n-octenylsuccinate starch; CM = cervical mucous; Cmax = peak plasma
drug concentration; CRF = chronic renal failure; CSM = cholestyramine; CVD = cerebrovascular disease; DM = diabetes mellitus; EFT =
effervescent tablet; FC = film coated; FCT = film-coated tablet; FHF = fair hepatic function; GA = gestational age; HL = hyperlipidaemia; HT
= hypertension; HU = hyperuricaemia; I400 = ibuprofen 400mg in one tablet; IC301 = ibuprofen 400mg and codeine 30mg in one combination
tablet; IC302 = ibuprofen 400mg and codeine 30mg in two separate tablets; IC601 = ibuprofen 400mg and codeine 60mg in one combination
tablet; IC602 = ibuprofen 400mg and codeine 60mg in two separate tablets; IV = intravenous; JRA = juvenile rheumatoid arthtitis; n = number
of participants; NR = not reported; NRCP = nerve root compression pain; OCS = oral contraceptive users; PHF = poor hepatic function; PINB
= premature infant newborn; R = R-enantiomer; S = S-enantiomer; SC = sugar coated; SGC = soft gelatin capsule; SR = sustained release;
tmax = time taken to achieve Cmax; UDS = underlying disease states (hypertension, gout, diabetes, arteriosclerotic cardiovascular disease
etc.) V = venous plasma; X = hydro-alchoholic solution (5% w/w) contained in a gel formulation prep; Y = hydrophilic ointment formulation 5%
w/w ibuprofen in a PEG-base; Z = oil-in water emulsion cream containing 5% w/w ibuprofen; 1 = Chinese; 2 and 3 = Shan Don Xin Hua
Pharmaceutical Factory; 4 = British Boots Company.
pharmacokinetics.[198] However, a follow-up study 8 fasted healthy volunteers. The scintigraphy stud-
suggests that, as compared with fasting administra- ies suggest that a sustained release ibuprofen
tion, intake of ibuprofen postprandially results in a formulation is absorbed throughout the entire GI
clear reduction of R-(–)- (~48%) and S-(+)- tract and that the large bowel is the site that
ibuprofen (≈25%) plasma concentrations mainly demonstrates the greatest proportion of ibuprofen
during the initial 3 hours post-dose. The ratio of absorption.[144] In 5 fed individuals, the sustained-
S-(+)/R-(–) ibuprofen post-prandially was also in- release tablet remained in the stomach and eroded
creased for Cmax and AUC.[212] Comparison of slowly over 7 to 12 hours resulting in gradual in-
maximal concentrations and areas under the con- creases in small bowel radioactivity. In the remain-
centration versus time curves between the first and ing 3 individuals, the intact tablet was ejected from
last doses demonstrate no evidence of accumula- the stomach and a gastric residence time of approx-
tion or time-dependency after multiple doses.[199] imately 4 hours was measured. However, there was
The relative bioavailability of a suspension no significant alteration in drug bioavailability.[153]
containing enteric-coated microcapsules, Another radiolabelled sustained release formu-
rapid-release film-coated tablet and a sustained relation was administered to volunteers with a light
lease tablet were compared and found to be bio- breakfast, fasted or with a heavy breakfast. Gastric
equivalent.[179] Compared with regular release tab- emptying was slowest with the heavy breakfast
lets, sustained and controlled release preparations group and in several individuals the unit remained
have a ≈ 3 to 6 times lower peak plasma drug intact in the stomach for >15 hours. Fasting indi-
concentration (Cmax) and ≈4 to 12 hours delayed viduals demonstrated the double peaking phenom-
tmax.[128,141,145,157,222,223] ena, whereas after a light breakfast a levelling of
External γ scintigraphy was used to monitor GI the 2 peaks to a plateau occurred, while after a
transit of radiolabelled sustained release tablets in heavy breakfast only a secondary peak was evi-
dent. The secondary peak appears to be due to dis- After percutaneous administration of a ibupro-
integration after 12 to 14 hours and a high absorp- fen 300mg cream a Cmax of 0.64 mg/L was demon-
tion in the ascending colon.[152] strated after 2 hours with a relative bioavailability
The effect of food on the pharmacokinetics of of 5% compared with oral tablets.[226] Topical ap-
sustained release ibuprofen administered was in- plication of ibuprofen gel demonstrates very low
vestigated as a single 800mg erodible sustained re- concentrations in plasma with a Cmax of 0.2 mg/L
lease matrix tablet after an overnight fast or along achieved about 11 hours after the topical applica-
with a heavy vegetarian breakfast. The formulation tion of 400mg with a percutaneous absorption of
exhibited multiple peaks in the plasma concentra- the gel of about 3% of the dose.[86] Percutaneous
tion-time curve. Food did not affect the bioavaila- application of ibuprofen gel preparation with oc-
bility, however, a statistically significant increase clusion for 2 hours compared with a standard tablet
in the concentration of the first peak from ≈14 preparation demonstrated a relative bioavailability
mg/L fasting to ≈20 mg/L with food.[181] of 22%.[178]
In a 4-way crossover study comparing an A comparison of 3 topical formulations in a gel,
ibuprofen 800mg tablet dissolved in water with or- hydrophilic ointment or emulsion cream demon-
ange juice and diluted cherry syrup solutions, no strated that the gel formulation has the highest con-
significant pharmacokinetic differences were ob- centrations in blood and this was reached in the
served for the orange juice solution, though a delay shortest time (5.83 hours), whereas the hydrophilic
in tmax was observed for the dilute cherry syrup ointment showed the lowest Cmax concentration
solution. A reduced tmax, Cmax and AUC were noted and this was reached at the slowest rate (7.0 hours).
with a Coca-Cola® solution. High sugar loads, The absorption of ibuprofen from an emulsion
causing a delay in gastric emptying, were postu- cream was less than that with the gel formulation
lated to contribute in the delay in ibuprofen absorp- but higher than the hydrophilic ointment.[173]
tion.[148] In an open study of 17 patients with degenera-
AUC versus dose plots from the ibuprofen 250 tive knee disorders requiring operations, the pene-
to 1200mg dosage range demonstrate a nonlinear tration and absorption of ibuprofen from a topical
relationship between total drug concentrations gel and oral tablets was assessed. Whereas oral
with dose and a more linear relationship between administration led to higher concentrations in
free concentrations. This non-linearity for total plasma, synovial fluid and fasciae, higher concen-
concentrations is characterised by a smaller than trations in muscle and subcutis were found after
expected increase in the AUC for the total drug topical administration 15 hours post-dose. Topical
dose. This non-linearity is possibly due to a satu- administration resulted in higher concentrations in
ration of protein binding rather than impaired ab- the fasciae, muscle and subcutis than those in the
sorption, as urinary recovery data appeared to be blood and synovial fluid.[225]
dose-independent.[125,129,206,224]
2.3 Inversion and Stereoisomerism
2.2 Topical Delivery
It has been suggested that the rate of oral ab-
There has been considerable interest in the de- sorption may also influence the pharmacokinetics
velopment of topical NSAIDs in recent years. of ibuprofen enantiomers. R-(–)-Ibuprofen under-
When applied topically, these drugs are formulated goes an unidirectional metabolic inversion to S-
to penetrate the skin barrier in sufficient amounts (+)-ibuprofen.[185,227,228] It has been suggested that
to reach the joints and muscles and exert therapeu- this inversion process is influenced by the rate of
tic activity. Dominkus et al.[225] have recently re- ibuprofen absorption although this remains a con-
viewed the studies concerning topical delivery of tentious finding.[188] If inversion takes place pre-
ibuprofen. systemically within the GI tract the longer the
118 Davies
ibuprofen resides within this inversion site the analysis of ibuprofen bioinversion and simulation,
more likely it is that the extent of inversion may using the S : R AUC ratio and making a comparison
increase.[188] A significant positive correlation be- with literature values, suggests systemic inversion
tween the tmax and the S : R concentration ratio has process.[232]
been observed.[188] The greater S : R AUC ratios in In a preliminary study of the racemate compared
individuals with longer tmax also suggest the possi- with the enantiomers [S-(+) 400mg, R-(–) 400mg,
bility that the absorption rate is dependent on racemic ibuprofen 800mg], the AUC of S-(+)-
ibuprofen enantiomer inversion.[186] In a further ibuprofen after racemate was 128 vs 93.1 mg/L • h
study, the S : R AUC ratios were demonstrated to as compared with S-(+)-ibuprofen. The AUC of R-
be unaffected by increasing the dose but were sig- (–)-ibuprofen was greater after R-(–)-ibuprofen ad-
nificantly greater (1.35) as compared with ibu- ministration (101 vs 82.3 mg/L • h) than after race-
profen solutions (1.15 to 1.24). This suggests that mic ibuprofen. These initial results suggest the
a longer residence time in the GI tract may allow possibility of altered kinetics due to the concurrent
more presystemic inversion.[197] administration of the respective optical antipode.[232]
Clearly systemic inversion contributes to the in- However, this study has relied upon simulation of
version process. Formation of S-(+)-ibuprofen af- published experimental data. In contrast, the data
ter intravenous administration of R-(–)-ibuprofen of Smith et al.[206] were similar in these 2 cases.
is strong evidence for systemic inversion. [229] In a triple crossover study [S-(+) 300mg, R-(–)
Furthermore, following intravenous and oral ad-
300mg, racemic ibuprofen 600mg] the inverted R-
ministration of racemic or R-(–)-ibuprofen the dif-
(–)-ibuprofen after racemate administration pro-
ferences between plasma concentrations of the
vided for only one-third of the AUC of S-(+)-
enantiomers appears to be negligible.[230] These
ibuprofen obtained after S-(+) administration.
studies have not determined whether or not sys-
Higher peak plasma concentrations of S-(+)-
temic inversion may also be saturable and further
ibuprofen were obtained after S-(+)-ibuprofen ad-
studies are required to clarify this.
ministration alone as compared with the racemate
A lack of presystemic inversion of R-(–)- to S-
(mean 19.05 versus 16.4 mg/L) with tmax (1.44 ver-
(+)-ibuprofen in humans has been suggested by
Hall et al.[201] In this study low dose racemic sus 1.8 hours), which did not reach any statistical
ibuprofen 400mg was administered orally (with a significance. The bioavailability of S-(+)-
tmax of 1.5 hours) and intravenously. There were no ibuprofen was independent of dose between 150
difference in AUC and other pharmacokinetic pa- and 500mg. [194] The formulation of S-(+)-ibu-
rameters between oral and intravenous doses. Over profen from a 400mg tablet was similar to that fol-
an 8-hour study period the total ibuprofen plasma lowing an aqueous solution. A linear relationship
concentration demonstrated a progressive enrich- between AUC and dose was evident for S-(+)-
ment in the content of the S-(+)-enantiomer, ibuprofen over a 200 to 600mg dosage range.[99]
suggesting a major systemic contribution to the in- In assessing the bioequivalence of an ibupro-
version process.[201] The bioavailabilities of R-(–)- fen formulation, it was found that the product
ibuprofen and total ibuprofen were 0.92 ± 0.11 and had bioequivalence parameters comparable with
0.95 ± 0.08, respectively. The S : R ratio is not an those of the standard tablet when assessment
ideal index of fractional inversion as it can be was based upon the measurement of the sum of the
influenced by protein binding in addition to the 2 enantiomers. However, examination of t h e
inversion process. An initial evaluation of ibu- S-(+)-ibuprofen enantiomer indicated a significant
profen bioinversion by simulation using plasma (≈38%) reduction in the Cmax after administration
concentration S : R ratio suggests the possibility of of the new product.[222] In addition, in assessing the
presystemic inversion.[231] However, a follow-up bioequivalence a generic product had 16% less R-
Table III. Pharmacokinetic properties of ibuprofen in healthy volunteers (oral immediate release dosage forms administered in single doses,
except where indicated)
n (patient group) Agea (y) [range] Dose [no. of days] t1⁄2β (h)b Vd/F (L/kg)b CL/F (L/h/kg)b Reference
Nonstereospecific studies
20 [22-50] 200mg 1.93 NR NR 16
18 [28-35] Study I: Ibuprofen 300mg capsule (Amersol®) 1.99 NR NR 121
Study I: Ibuprofen 300mg tablet (Motrin®) 1.67 NR NR
Study I: Ibuprofen 300mg solution 1.52 NR NR
20 [20-33] Study II: Ibuprofen 400mg capsule (Amersol®) 1.90 NR NR
Study II: Ibuprofen 200mg capsule (Amersol®) 1.78 NR NR
8 [19-35] Ibuprofen 400mg 1.5 NR NR 122
Ibuprofen 400mg (Dolgit®) 1.5 NR NR
15 25 [22-35] Ibuprofen 400mg tablets 2.54 NR 0.0419 125
Ibuprofen 2 × 400mg tablets 2.28 NR 0.0498
Ibuprofen 3 × 400mg tablets 2.17 NR 0.0541
Ibuprofen 400mg solution 1.87 NR 0.0426
20 28 [19-42] 400mg Ibuprofen Q6H for 8 doses 1.93 0.142 0.05 127
400mg Ibuprofen and 650mg Paracetamol Q6H 1.87 0.139 0.051
for 8 doses
4 39.5 [31-47] Ibuprofen 400mg 1.90 C NR NR 38
2.19 V NR NR
17 70 [65-78] Ibuprofen 400mg 2.12 0.147 0.0468 129
Ibuprofen 800mg 2.21 0.167 0.0524
Ibuprofen 1200mg 2.11 0.204 0.0654
7 Young male 34.3 [20-88] Ibuprofen 600mg 1.92 0.17 0.062 131
(out of 37)
10 Young 26.6 [20-88] Ibuprofen 600mg 2.29 0.19 0.059
female (out of
37)
11 Elderly male 67.1 [20-88] Ibuprofen 600mg 2.43 0.18 0.052
(out of 37)
9 Elderly female 71.0 [20-88] Ibuprofen 600mg 2.33 0.18 0.055
(out of 37)
10 24 [22-27] Ibuprofen 600mg 2.07 NR NR 130
Ibuprofen 600mg + 1g Sucralfate qid the day 2.20 NR NR
before the study and 1g on the morning of the
study
6 [23-32] cimetidine 300mg Q6h for 1 week and 1.92 NR NR 135
Ibuprofen 400mg
Ibuprofen 400mg 1.9 NR NR
8 23 [17-32] Ibuprofen 600mg resinated granules 1.7 0.22 0.091 133
Ibuprofen 600mg microincapsulated granules 2.0 0.28 0.104
13 [23-31] Ibuprofen 400mg 2.1 0.14 0.048 134
Cimetidine tid 400mg tid 48h before ibuprofen 2.11 0.13 0.044
and continuing during study
Ranitidine 150mg bid 48h before ibuprofen and 2.01 0.14 0.049
10 [21-47] Ibuprofen 600mg 1.95 0.16 0.057 134
Sucralfate 1g 2 days prior qid and Ibuprofen 2.03 NR NR
400mg with 1g Sucralfate and 2 addtional 1g
tablets during the experiment
Continued over page
120 Davies
Table III. Contd

6 23.6 [18-33] Ibuprofen 300mg SCT tablets 2.31 0.21 0.072 138
Ibuprofen 400mg SCT tablets 1.81 0.16 0.066
Ibuprofen 600mg coated tablets 2.99 0.21 0.06
Ibuprofen 400mg with concurrent antacid 1.84 NR NR
suspension (62ml) Al + Mg(OH)2 ibuprofen 1.80 NR NR
400mg with antacid suspension administered
1h after ibuprofen
Ibuprofen 400mg with concurrent antacid 1.79 NR NR
suspension and then 3 more doses of antacid
given every 5h
Nizatidine 300mg nightly for 6 days + Ibuprofen 2.24 NR NR
400mg on day 3
Cimetidine 800mg nightly for 6 days and 2.47 NR NR
Ibuprofen 400mg on day 3
17 [18-24] 600mg Brufen® 2.0 NR NR 147
600mg Burana® 2.2 NR NR
600mg Ibumetin® 1.9 NR NR
8 28 [25-37] 800mg Ibuprofen + 120ml water 1.82 NR NR 148
800mg Ibuprofen dissolved in Coca-Cola® 1.98 NR NR
800mg dissolved in orange juice 1.82 NR NR
800mg Ibuprofen dissolved in diluted cherry 1.98 NR NR
syrup
12 25 [18-55] Phase I: Ibuprofen 600mg qid × 3 days, day 4 1.75 NR 0.056 149
Ibuprofen 600mg in the morning
Phase II: Ibuprofen 600mg qid and ranitidine 1.92 NR 0.053
HCl 300mg × 3 days with breakfast, day 4
300mg Rantidine 2h before Ibuprofen 600mg
Phase III: Ibuprofen 600mg qid and ranitidine 1.85 NR 0.048
HCl 300mg × 3 days with breakfast, day 4
800mg cimetidine 2h before Ibuprofen 600mg
8 24 800mg Sodium Ibuprofen solution orally 1.97 NR NR 150
Aluminum Ibuprofen 800mg suspension orally 3.28 NR NR
Sodium Ibuprofen 800mg solution rectally 2.01 NR NR
800mg Aluminum Ibuprofen suspension rectally 1.89 NR NR
8 27 [25-39] 1000mg Imbun® fasted 1.89 0.19 0.051 220
600mg Dolgit® fasted 1.80 0.11 0.042
1000mg Imbun® fed 1.87 0.12 0.052
600mg Dolgit® fed 1.80 0.13 0.051
16 28.9 Ibuprofen 600mg SCT 1.8 NR NR 158
Ibuprofen 600mg FCT 1.4 NR NR
8 29.8 Ibuprofen 200mg slow IV 1.58 0.17 0.048 87
Ibuprofen 400mg slow IV 1.57 0.16 0.05
Ibuprofen lysine 500mg 2.03 NR NR
14 23.14 [21-25] Ibuprofen 400mg FCT 1.55 NR NR 162
Ibuprofen 400mg SGC 1.42 NR NR
Ibuprofen 400mg EFT 1.21 NR NR
Table III. Contd

6 21.3 [21-23] Ibuprofen 800mg 1.7 NR NR 163
1.0 CM NR NR
Ibuprofen 600mg and misoprostol 200μg 1.85 NR NR
Ibuprofen 600mg and ranitidine HCl 1.78 NR NR
8 37.2 Ibuprofen 200mg sachets 1.91 0.11 0.041 166
Ibuprofen 200mg tablets 2.38 0.14 0.41
Ibuprofen 400mg sachets 1.85 0.123 0.049
8 32.1 Ibuprofen 400mg tablets 1.95 0.166 0.049
49 Febrile [0.25-12] Ibuprofen 8 mg/kg 1.6 NR NR 168
6 35.3 [29-39] Ibuprofen 400mg 2.15 NR NR 174
Ibuprofen 400mg and Colestipol HCl 10g 2.16 NR NR
Ibuprofen 400mg and CSM 8g 2.22 NR NR
24 [18-50] I400 2.13 NR 4.27 175
IC301 2.16 NR 4.26
IC302 2.37 NR 4.21
IC601 2.12 NR 4.14
IC602 2.19 NR 4.59
18 30.2 [22-41] 600mg Profinal® 2.79 NR NR 177
600mg Brufen® 2.69 NR NR
18 26.3 [20-38] Ibuprofen 500mg topically 2.5 NR NR 178
Ibuprofen 400mg tablet 2.5 NR NR
9 26.7 Ibuprofen 800mg rapid release 2.10 NR NR 179
Ibuprofen 800mg SR 3.79 NR NR
Ibuprofen 800mg supension 1.87 NR NR
18 NR Ibuprofen 400mg 2.11 NR NR 182
Ibuprofen 400mg 1.99 NR NR
Stereospecific studies
4 [31-45] S-Ibuprofen 400mg solution 1.71 S NR NR 185
R-Ibuprofen 400mg solution 2.03 R NR NR
Racemic Ibuprofen 800mg solution 1.67 R NR NR
2.50 S NR NR
2 NR 200mg 1.9 S NR NR 82
1.4 R NR NR
12 [18-34] Ibuprofen 400mg tablet (Apotex) 2.24 R NR NR 186
2.77 S NR NR
Ibuprofen 400mg (Motrin®) 1.41 R 0.12 R 0.054 R
2.24 S NR S NR S
14 [19-37] Motrin® 600mg FCT 2.63 S NR NR 188
8 600mg 2.69 R NR NR
Apo-Ibuprofen® 600mg FCT 2.58 S NR NR
8 600mg 2.84 R NR NR
Motrin® 300 mg SCT 2.42 S NR NR
6 2.02 R NR NR
Apo-Ibuprofen® 300mg SCT 2.21 S NR NR
6 2.24 R NR NR
4 26.75 [22-36] R-Ibuprofen 300mg + R-[2H3] 1.632 R 0.12 R 0.06 R 190
1.93 S
Continued over page
122 Davies
Table III. Contd

Ibuprofen 304mg solution 1.59 0.11 R[2H3] 0.061 R[2H3]
R[2H3]
1.97
S[2H3]
6 [25-38] Ibuprofen 600mg 1.40 R NR NR 191
1.64 S NR NR
Cimetidine 400mg bid for 3 days then ibuprofen 1.46 R NR NR
600mg + cimetidine 400mg bid 1.93 S NR NR
24 22.6 [21-25] Ibuprofen 400mg 2.03 R 0.21 R 0.071 R 192
3.05 S
3 Ibuprofen 200mg 1.71 R 0.15 R 0.060 R
2.3 S
6 Ibuprofen 400mg 1.72 R 0.138 R 0.066 R
2.63 S
3 Ibuprofen 800mg 1.6 R 0.169 R 0.073 R
2.5 S
4 [23-28] Ibuprofen 200mg 1.86 R NR NR 193
1.93 S NR NR
Ibuprofen 400mg 3.23 R NR NR
3.36 S NR NR
1.95 S NR NR
2.01 S NR NR
11 [25-47] Study I: S-Ibuprofen 300mg 2.09 S NR NR 194
Study I: R-Ibuprofen 300mg 2.10 R NR NR
2.22 S NR NR
Study I: Ibuprofen 600mg racemate 2.29 R NR NR
2.26 S NR NR
Study II: S-Ibuprofen 150mg 1.85 S NR NR
4 Study II: S-Ibuprofen 500mg 2.24 S NR NR
4 [24-37] Ibuprofen 200mg tablet 7.9 R 1.5 R 66 R 222
10.8 S 1.5 S 135 S
Ibuprofen 300mg controlled release capsule 6.9 R 2R 104 R
7.8 S 2S 160 S
16 NR S-Ibuprofen 130mg 1.07 S NR NR 196
R-Ibuprofen 130mg 1.5 R NR NR
3.03 S NR NR
Racemic Ibuprofen 200mg 1.31 R NR NR
2.49 S NR NR
6 [32-44] Ibuprofen 50mg solution 2.15 R NR 0.059 S 197
2.81 S NR
Ibuprofen 100mg solution 2.24 R NR 0.063 S
2.90 S NR
2.09 S NR
2.07 S NR
Table III. Contd

2.19 S NR
Ibuprofen 1200mg solution 2.53 R NR 0.081S
2.22 S NR
Ibuprofen 600mg tablet 2.08 R NR 0.083 S
2.03 S NR
11 NR Ibuprofen 600mg fasted 1.65 R NR NR 198
2.1 S
Ibuprofen 600mg fed 1.31 R NR NR
2.24 S
Sucralfate 1g qid × 2 days then ibuprofen 1.73 R NR NR
600mg 2.1 S
12 23.6 [19-27] Ibuprofen 600mg 3.2 R 0.47 R 0.096 R 199
3.1 S
Ibuprofen 400mg q8h for 5 days 2.23 R 0.35 R 0.10 R
2.48 S
10 [19-30] Ibuprofen 400mg orally + 10mg S-d4-ibuprofen 2.82 R NR 0.051 R CLR 201
2.57 S NR 0.029 R CLinv
2.26 NR 0.021 R
S-d4 CLnoninv
0.044 S
0.066 S-d4
Ibuprofen 400mg + 10mg S-d4-ibuprofen IV 3.3 R NR 0.046 R CLR
2.82 S NR 0.026 R CLinv
1.96 NR 0.02 R CLnoninv
S-d4
0.042 S
0.068 S-d4
8 52 [46-59] Ibuprofen 600mg 1.7 R NR NR 203
1.8 S NR NR
8 50 [46-61] S-Ibuprofen 400mg 2.6 S NR NR
5 25 [21-39] Ibuprofen 1200mg 3.2 R NR 0.085 R 204
3.2 S NR
12 23 [20-29] R-Ibuprofen 300mg solution 1.8 R 0.12 R 0.047 R 206
2.75 S NR NR
S-Ibuprofen 300mg solution 1.73 S 0.16 S 0.065 S
R-Ibuprofen 300mg + 300mg S-ibuprofen 1.68 R 0.14 R 0.058 R
solution 2.4 S NR NR
R-Ibuprofen 300mg + S-Ibuprofen 600mg 2.58 R 0.14 R 0.061 R
solution 2.23 S NR NR
9 Young patients 29.2 [20-34] Ibuprofen 800mg 1.7 R NR NR 208
3.1 S NR NR
9 Elderly patients 55.4 [44-63] Ibuprofen 800mg 3.4 R NR NR
3.1 S NR NR
18 [21-36] Racemic Ibuprofen 400mg 1.94 R NR NR 99
2.00 S NR NR
S-Ibuprofen 200mg Racemic 800mg 1.65 S NR NR
S-Ibuprofen 400mg racemic 1200mg 2.18 R NR NR
1.99 S NR NR
Continued over page
124 Davies
Table III. Contd

1.61 S NR NR
S-Ibuprofen 600mg 2.31 R NR NR
2.00 S NR NR
1.79 S NR NR
8 28 [24-34] Ibuprofen 800mg + S-d4-ibuprofen 10mg 4.18 R 0.6 R 0.055 R Inv 233
2.98 S 0.19 S 0.040 R NInv
1.88 0.071 SD4
SD4
Ibuprofen 800mg q6h × 30 days + 6.43 R 1.03 R 0.075 R Inv
S-d4-ibuprofen 10mg 3.73 S 0.17 S 0.053 R NInv
1.67 0.071 SD4
SD4
14 73 [65-80] Ibuprofen 800mg + S-d4-ibuprofen 10mg 4.2 R 0.46 R 0.047 R Inv
2.78 S 0.17 S 0.030 RNInv
2.05 0.062 SD4
SD4
Ibuprofen 800mg q6h × 30 days + 8.35 R 1.03 R 0.054 R Inv
S-d4-ibuprofen 10mg 3.87 S 0.16 S 0.029 RNInv
1.97 0.058 SD4
SD4
13 75 [66-87] Ibuprofen 800mg + S-d4-ibuprofen 10mg 3.47 R 0.39 R 0.047 R Inv
3.25 S 0.22 S 0.04 RNInv
2.42 0.069 SD4
SD4
Ibuprofen 800mg q6h × 30 days + 5.5 R 0.78 R 0.055 RInv
S-d4-ibuprofen 10mg 4.33 S 0.24 S 0.052 RNInv
2.45 0.073 SD4
SD4
8 Female 24 R-Ibuprofen 6 mg/kg 1.7 0.17 0.063 210
8 Female OCS 22 1.6 0.17 0.065
8 Male 21 1.7 0.18 0.065
18 27.4 [24-36] Ibuprofen 400mg fasting 1.57 R NR NR 212
2.04 S NR NR
Ibuprofen 400mg postprandial 1.79 R NR NR
2.14 S NR NR
6 NR Ibuprofen 400mg tablets 1.33 R 0.106 R 0.057 R 215
2.18 S 0.123 S 0.041 S
7 25.6 A: 400mg S-[+]ibuprofen arginine in 150ml H20 1.75 NR NR 213
B: 400mg R-(–)-ibuprofen arginine in 150ml H20 1.63 R NR NR
2.47 S NR NR
C: 400mg (±)-ibuprofen arginine in 300ml H20 2.28 R NR NR
2.14 S NR NR
Abbreviations: C = capillary plasma; CL/F = plasma clearance of drug after oral administration; CLinv = inversion clearance of R-ibuprofen;
CLnoninv = noninversion clearance of R-ibuprofen; CLR = total clearance of R-ibuprofen; CM =cervical mucous; CRF = chronic renal failure;
CSM = cholestyramine; EFT = effervescent tablet; FCT = film-coated tablet; I400 = ibuprofen 400mg in one tablet; IC301 = ibuprofen 400mg
and codeine 30mg in one combination tablet; IC302 = ibuprofen 400mg and codeine 30mg in two separate tablets; IC601 = ibuprofen 400mg
and codeine 60mg in one combination tablet; IC602 = ibuprofen 400mg and codeine 60mg in two separate tablets; n = number of subjects
or patients in study; NR = not reported; R = R-enantiomer; RS = racemate; S = S-enantiomer; SCT = sugar coated tablet; SGC = soft gelatin
capsule; t1⁄2β = elimination half-life; V = venous plasma; Vd/F = apparent volume of distribution after oral administration.
(–)-enantiomer bioavailable compared with the mg/L, ibuprofen appeared to be less strongly
brandname product.[186] bound to rheumatoid plasma which may be the
S-(+)-Ibuprofen and R-(–)-ibuprofen adminis- consequence of lower albumin concentrations
tered alone rapidly reached significantly higher (51 g/L in normal versus 46 g/L in rheumatoid).[31]
Cmax than after the same dose of racemate. No The protein binding of ibuprofen in patients
significant differences were observed in the phar- with rheumatoid and osteoarthritis demonstrated
macokinetic parameters of S-(+)-ibuprofen after no significant difference between these groups in
single and multiple doses.[194] the free fractions of ibuprofen.[238] In addition, the
overall free fraction in plasma is not influenced by
2.4 Distribution age or gender.[131]
The apparent volume of distribution (Vd/F), de- Competitive plasma binding between the en-
termined after oral administration, was between antiomers of ibuprofen has been suggested.[48] Us-
6.37 and 23.51L in humans (0.1 to 0.2 L/kg) which ing site I and II specific fluorescent probes, the
approximates plasma volume and suggests tissue binding of enantiomers was investigated, but no
binding is appreciably less than plasma protein significant difference was found. Utilising a
binding, and is consistent with that of other 2-APA stereospecific GC-MS assay with equilibrium di-
NSAIDs (table III).[9-11,14-15] The Vd/F based on alysis showed that both R-(–)- and S-(+)-ibuprofen
total concentrations increases significantly with had saturable binding with a mean ratio of free con-
dose; however, there is a lack of dose-related centrations of S : R of 1.7 over a concentration
changes in free drug Vd/F (see table IV).[235] range of 2 to 100 mg/L.[247] There is an absence of
nonlinear protein binding for the enantiomers of
2.4.1 Protein Binding
ibuprofen at relatively low dose.[248] At low doses
Ibuprofen is extensively (>98%) bound to
(400mg) there were no significant differences be-
whole human plasma and purified albumin at ther-
tween oral and intravenous serum protein binding
apeutic concentrations.[2,32,115,132,206,207,224,236,238]
The association constant for the binding of ibupro- for R-(–) and S-(+)-ibuprofen.[201]
fen to purified human serum albumin (HSA) has Protein binding of ibuprofen enantiomers is
been reported to be in the range of 105 to 106 stereoselective with greater fraction of S-(+)-
L/mol[132,237,239,241-243] and is primarily bound to ibuprofen unbound.[192,193,201,248] The percentage
site II of the albumin molecule.[240,241,244] unbound of each ibuprofen enantiomer was
Stereoselective protein binding studies suggest concentration-dependent over the therapeutic con-
that there may be at least 3 different binding sites centration range of 1 to 50 mg/L and also influ-
for ibuprofen with different enantioselectivit- enced by the presence of its optical antipode.[248]
ies.[245] A subsequent study demonstrates that R-(–) Because of the saturation of plasma protein bind-
and S-(+)-ibuprofen had 1 common binding site to ing there is an apparent decrease in AUC/dose val-
HSA and that S-(+)-ibuprofen has a least 1 other ues after higher doses, which contributes to non-
major binding site.[246] linear kinetics of ibuprofen.[125,235,243] In a dose
The fraction of ibuprofen not bound to HSA ranging study between 50 to 1200mg of ibuprofen
increased significantly from a value of 0.033 at a the AUC versus dose relationship were nonlinear
concentration of 2 mg/L to a value of 0.042 at at higher doses. A gradual increase in the apparent
50 mg/L. In parallel to these findings the fraction clearance of both enantiomers with comparable
of ibuprofen not bound to plasma proteins in- S : R AUC ratios suggests a non-stereoselective
creased significantly from 0.0128 at a concentra- parallel saturation of plasma protein binding
tion of 2 mg/L to 0.0155 at 50 mg/L. Comparing sites.[197]
plasma from healthy individuals and those with In a subsequent study[201] in which 3 individuals
rheumatoid arthritis at concentrations of 2 and 50 received orally administered racemic ibuprofen
126 Davies
Table IV. Pharmacokinetic properties of ibuprofen in patients (ibuprofen was administered as an immediate release dosage formulation in
single doses except where indicated)
n (patient group) Agea (y) Dose t1⁄2β Vd/F CL/F Reference
[range] [no. of days] (h)b (L/kg)b (L/h/kg)b
Nonstereospecific studies
5 Healthy individuals NR Ibuprofen 400mg 1.86 NR NR 116
4 with Arthritis NR Ibuprofen 400mg 1.28 NR NR
17 with JRA 11 Ibuprofen 40 mg/kg 2.3 NR NR 118
8 RA NR Ibuprofen 400mg qid - dose 1 1.09 NR NR 123
Ibuprofen 400mg qid - day 7 0.99 NR NR
Ibuprofen 400mg qid - day 14 1.00 NR NR
9 FHF (out of 15 with ALD) 54.3 Ibuprofen 400mg 1.9 NR NR 124
6 PHF (out of 15 with ALD) 53.0 Ibuprofen 400mg 2.6 NR NR
29 Healthy individuals Ibuprofen 400mg 2.2 NR NR
11 Obese 35 Ibuprofen 600mg 2.00 0.138 0.044 132
36 Ibuprofen 600mg 2.14 0.176 0.058
8 CRI [20-48] Ibuprofen 600mg 2.05 0.22 0.0912 234
8 RA 54.125 [26-67] Ibuprofen 600mg tid × 2 days and 7am 1.66 NR NR 139
day 3 - day 1
Ibuprofen 600mg tid × 2 days and 7am 2.02 NR NR
day 3 - day 3
9 Paediatric fever (out of 17) 6.7 [3.1-9.6] Ibuprofen 5mg/kg 1.6 NR 0.072 160
8 Paediatric fever (out of 17) 6.2 [3.1-9.6] Ibuprofen 10 mg/kg 1.6 NR 0.084
38 Febrile children [0.25-12] Ibuprofen 5 mg/kg 1.65 0.182 0.089 165
46 Febrile children Ibuprofen 10 mg/kg 1.48 0.217 0.099
13 CF [6-11] Ibuprofen 300mg 1.42 0.211 0.108 159
4 Ibuprofen 400mg 1.55 0.282 0.126
Ibuprofen 600mg 1.57 0.237 0.114
13 CF [8-11] Ibuprofen 13.4 mg/kg 1.53 0.291 0.138
4 [8-11] Ibuprofen 13.29 mg/kg 1.43 0.158 0.078
10 Haemophiliacs 33 Ibuprofen 400mg acute 1.79 NR 0.037 171
Ibuprofen 400mg q6h for 2 weeks 1.84 NR 0.039
5 Healthy individuals 29 Ibuprofen 400mg 1.81 NR 0.033
18 Febrile children 5.8 Ibuprofen 6 mg/kg 1.97 0.164 0.0576 169
Group I: 5 burn patients (out of 20 Enteral feeding 1.4 NR NR 172
total of 10)
Group II: 5 burn patients (out of 38 Hospital diet 5.1 NR NR
total of 10)
11 Infants [0.5-1.5] Ibuprofen 7.6 mg/kg syrup 1.6 0.2 0.11 176
16 CF (out of 20) 11.5 [1-42] Ibuprofen tablets 25.8 mg/kg 1.55 0.259 0.126 75
4 CF (out of 20) Ibuprofen elixir 25.3 mg/kg 1.12 0.216 0.138
21 PINB GA 26.8 [22-31 Ibuprofen lysinate10 mg/kg IV 30.5 0.621 0.00206 183
weeks]
18 Dental 28.4 Ibuprofen 400mg 1.58 NR NR 184
Stereosepecific studies
8 RA 58.38 [28-61] Ibuprofen 800mg 1.6 R 0.16 R 0.068 R 187
2.3 S 0.086 S
8 with Arthritis 49.75 [28-55] Ibuprofen 800mg q8h for 3 days 1.78 R NR 0.09 R 195
1.98 S NR 0.06 S
18 Febrile children 5.8 Ibuprofen 6 mg/kg 1.47 R 0.158 R 0.0744 R 169
2.31 S 0.248 S 0.0744 S
39 Knee OA (out of a 45 patient 58 [31-87] Ibuprofen 300mg qid × 4 days 2.8 R NR 0.053 R 200
group) 3.1 S NR 0.057 S
6 Hip OA (out of a 45 patient Ibuprofen 600mg qid × 4 days 2.9 R NR 0.07 R
group) 3.0 S NR 0.078 S
15 Ibuprofen 300mg 1.7 R NR 0.064 R
Table IV. Contd

n (patient group) Agea (y) Dose t1⁄2β Vd/F CL/F Reference
[range] [no. of days] (h)b (L/kg)b (L/h/kg)b
2.0 S NR 0.075 S
Ibuprofen 600mg 2.3 R NR 0.063 R
3.5 S NR 0.08 S
Group I: 25 with RA (out of a total 60 S-Ibuprofen 400mg tid × 14 days 1.9 S NR 0.077 S 202
of 50)
Group II: 25 with RA (out of a total 56 Racemic ibuprofen 600mg tid × 14 days 2.0 R NR 0.075 R
of 50) 2.1 S NR
8 Cirrhosis 56.25 [42-68] Ibuprofen 600mg 3.1 R NR NR 203
3.4 S NR NR
8 Cirrhosis 51.63 [41-62] S-Ibuprofen 400mg 1.6 S NR NR
1.7 R NR NR
10 Renal failure 60.2 Ibuprofen 800mg 2.9 R NR NR 205
4.7 S NR NR
11 UDS 62.2 Ibuprofen 800mg 2.9 R NR NR
4.2 S NR NR
10 Controls 57.9 Ibuprofen 800mg 3.1 R NR NR
3.3 S NR NR
11 Infants [0.5-1.5] 7.6 mg/kg syrup 1.5 R 0.3 R 0.12 R 176
1.6 S NR NR
46 Nerve-root compression pain [25-88] Ibuprofen 400mg × 2 tablets 1.7 NR NR 207
10 person control group 59.9 Ibuprofen 800mg 3.1 R NR NR 209
3.3 S NR NR
32 DM 62.6 Ibuprofen 800mg 3.2 R NR NR
7.7 S NR NR
HT Ibuprofen 800mg 3.1 R NR NR
6.3 S NR NR
HL Ibuprofen 800mg 3.5 R NR NR
3.3 S NR NR
HU Ibuprofen 800mg 4.3 R NR NR
2.6 S NR NR
CAD Ibuprofen 800mg 3.9 R NR NR
5.8 S NR NR
CVD Ibuprofen 800mg 3.6 R NR NR
4.4 S NR NR
CHF Ibuprofen 800mg 3.9 R NR NR
4.3 S NR NR
CRF Ibuprofen 800mg 3.5 R NR NR
4.5 S NR NR
Abbreviations: ALD = advanced liver disease; β-CD = β-cyclodextrin; CAD = coronary artery disese; CF = cystic fibrosis; CHF = congestive
heart falure; CL = plasma clearance of drug; CL/F = plasma clearance of drug after oral administration; CRF = chronic renal failure; CRI =
chronic renal insufficiency; CVD = cerebrovascular disease; Da = during attack; DM = diabetes mellitus; E = elderly; GA = gestational age;
Group I = 54 ± 16% body surface area (BSA) burn, 26 ± 16% full-thickness BSA burn; Group II = 40 ± 9% BSA burn, 9 ± 10% full-thickness
BSA; HL = hyperlipidaemia; HT = hypertension; HU = hyperuricaemia; JRA = juvenile rheumatoid arthritis; Mig = migraine; Ooa = out of attack;
PINB = premature infant new born; qd = daily; qid = 4 times daily; q6h (q12h) = every 6 (12) hours; RA = rheumatoid arthritis; t1⁄2β = elimination
half-life; UDS = underlying disease states (hypertension, gout, diabetes, arteriosclerotic cardiovascular disease etc.); Vd = apparent volume
of distribution; Vd/F = apparent volume of distribution after oral administration.
200 to 800mg, a progressive increase in clearance lationship was observed for R-(–) enantiomer.[201]
of the R-(–) enantiomer was also detected. A linear In addition, racemic ibuprofen 200 to 1200mg
relationship between drug dose and AUC was ob- were administered to 4 individuals and the AUC of
tained for S-(+)-ibuprofen, while a curvilinear re- the total and protein unbound enantiomers were
128 Davies
measured. With R-(–)-ibuprofen there was a de- ibuprofen was higher in serum than in synovial
crease in AUC/dose as the dose was increased. The fluid for up to 150 minutes after administration of
unbound fraction of S-(+)-ibuprofen was greater the dose, but thereafter the majority of patients had
than that of R-(–)-ibuprofen, although the AUC un- higher concentration of the drug in synovial
bound versus dose values of the enantiomers re- fluid.[251] In children with juvenile rheumatoid ar-
mained unchanged.[193] thritis, a total daily dose of 40 mg/kg 3 times daily
Finally, protein binding and competitive inhibi- led to peak concentrations in the synovial fluid 5
tion parameters of R-(–) and S-(+)-ibuprofen were to 6 hours after administration. Thereafter the sy-
determined in vivo in healthy volunteers.[224] Indi- novial fluid concentrations were higher than in se-
viduals were administered R-(–)-ibuprofen 300mg, rum.[117,218] Similar S : R concentration ratios in
S-(+)-ibuprofen 300mg, R-(–)-ibuprofen 300mg + synovial fluid and plasma have been reported for
S-(+)-ibuprofen 300mg, and R-(–)-ibuprofen 300mg ibuprofen in patients with arthritis and chronic
+ S-(+)-ibuprofen 600mg. The binding of each en- knee effusions. Maximal synovial fluid concentra-
antiomer was stereoselective and mutually compet- tions of both R-(–) and S-(+)-ibuprofen were less
itive, as well as nonlinear. However, no difference than maximal concentrations in the plasma.[187,195]
was observed in the binding capacity as a function The steady-state AUC in synovial fluid was signif-
of chirality. The intrinsic binding of R-(–)-ibupro- icantly correlated with the corresponding serum
fen was greater than that of S-(+)-ibuprofen and the values after the differences between the 2 fluids
unbound fraction was greater for S-(+)-ibuprofen with respect to albumin concentration were cor-
versus R-(+)-ibuprofen after a given dose of R-(–)- rected. Binding of ibuprofen to albumin and the
ibuprofen or racemate. Bound-free plasma concen- serum-synovial fluid albumin ratio has been sug-
trations of ibuprofen enantiomers were best de-
gested to control the steady-state distribution into
scribed by a single class of binding sites.[224]
synovial fluid.[195]
More recent studies have employed quantita- Free and total ibuprofen concentrations in se-
tive circular dichroism to the binding of the en- rum and synovial fluid were determined in patients
antiomers of ibuprofen to human serum albu-
with arthritis after ibuprofen 400mg 3 times daily
min.[249] In agreement with values obtained by
for 2 days. The total concentrations of ibuprofen in
microcalorimetry,[250] S-(+)-ibuprofen was found
the synovial fluid were about half that of serum.
to bind more tightly with an apparent binding con-
The ratio of total ibuprofen in synovial fluid to that
stant (Kapp) 8.0 ± 0.11 × 105 L/mol versus 4.8 ± 0.07
in serum correlated with the albumin concentration
× 105 L/mol for R-(–)-ibuprofen and 1.4 ± 0.04 ×
ratio suggesting that albumin binding is an impor-
105 L/mol for the racemate. S-(+)-Ibuprofen also
tant determinant in ibuprofen transynovial distri-
appears to have a greater ability to displace diaze-
pam from its binding site than racemic ibupro- bution.[254] The free ibuprofen in synovial fluid did
fen.[249] not significantly differ from the free serum concen-
trations which suggest that the synovium is readily
2.4.2 Distribution into Synovial Fluid accessible to unbound drug species.[252] Pharmaco-
The synovial membrane is the proposed pri- kinetic modelling suggest that ibuprofen enters the
mary site of action for NSAIDs in patients with synovial fluid compartment in the unbound form,
rheumatoid arthritis. Substantial concentrations whereas diffusion out of the synovial fluid may
of ibuprofen have been detected in synovial involve protein-bound ibuprofen.[253]
fluid.[117,118,187,206,252-254] In patients with rheuma- Ibuprofen concentrations were measured after
toid and osteoarthritis, ibuprofen had a longer tmax, the administration of a single dose and at steady
a lower C max and a higher elimination half-life state in 8 patients with rheumatoid arthritis. Seven
(t1⁄2β) in synovial fluid than in plasma. After a single hours after a steady-state dose, the mean synovial
dose of ibuprofen 400mg, the concentration of fluid plasma concentration ratios were constant
and the synovial fluid concentrations were on in the plasma (1.5 hours) and at lower concentra-
average somewhat greater than in plasma. Protein tions. The estimated t1⁄2β of R-(–) and S-(+)-
binding was greater in plasma than in synovial ibuprofen were 1.7 and 2.5 hours in plasma and 3.9
fluid because of lower albumin and total protein and 7.9 hours in the CSF, respectively. The CSF
concentrations in synovial fluid.[132] concentrations of both enantiomers were higher
than their concurrent free plasma concentrations
2.4.3 Distribution into Other Tissues from 1.5 to 8 hours. The AUC CSF/AUC free
Animal studies have suggested that chiral 2- plasma ratios were 2.6 and 3.3 for R-(–) and S-(+)-
APA derivatives may form unusual glycerolipids ibuprofen, respectively.[207]
by replacing fatty acid moieties in natural triglyc-
A single oral dose of ibuprofen 1200mg was
erides.[255] This distribution and uptake into adi-
administered to healthy volunteers with skin-blis-
pose tissue appears to occur during the inversion
ters that simulate a joint effusion. Concentrations
of the R-(–) to S-(+)-enantiomer, when coenzyme
were consistently higher for S-(+)-ibuprofen than
A thioesters are formed and are stereoselective for
R-(–)-ibuprofen in both plasma and blister fluid.
the R-(–) enantiomer. The extent of inversion,
Peak blister fluid concentrations were less than
therefore, may effect the uptake into adipose tis-
plasma concentrations [8.7 S-(+), 7.3 R-(–) vs 35.4
sue.[256]
S-(+), 25.4 R-(–) mg/L]. The tmax in blister fluid
It has been suggested that hybrid triglycerides
were identical for both enantiomers (5 hours) but
may disrupt normal lipid metabolism and mem-
considerably delayed compared with plasma (1.8
brane function and, therefore, abnormal lipid up-
hours). Blister fluid concentrations equalled and
take may be responsible for central nervous system
(CNS) adverse effects. However, NSAIDs have exceeded plasma concentrations at a mean of 5.5
recently shown promise in the treatment of Alz- hours for the R-(–)-ibuprofen and at 6 hours post-
heimer’s disease. It is not known whether the in- dose for S-(+)-ibuprofen. There was a relatively
version phenomena and stereoselective distrib- slow diffusion of drug out of blister fluid; thus, the
ution may influence the clinical outcome of blister fluid behaved pharmacokinetically as a pe-
racemic NSAIDs in the treatment of Alzheimer’s ripheral compartment for drug distribution, simi-
disease. Currently, the promise of NSAID use in larly to synovial fluid, and maintained relatively
Alzheimer’s disease relies mostly on epidemiolog- constant drug concentrations.[252]
ical studies, without any detailed information A follow-up study was undertaken in both sy-
about drug, dose or duration of treatment in the novial fluid and blister fluid in the same patients,
previous years. However, the mechanism respon- which demonstrated that the mean AUC S-(+)-
sible for this effect is yet unclear, but could involve ibuprofen was greater than AUC R-(–)-ibuprofen
anti-inflammatory aspects, since this disease was in both blister fluid and synovial fluid. The concen-
qualified as an ‘arthritis of the brain’.[257] trations of both enantiomers in both fluids were
Concentrations of ibuprofen in cervical mucus initially lower than those in plasma but exceeded
have been measured after oral administration to the plasma concentrations after about 4 to 8 hours.
healthy females. The concentration in cervical However, the kinetics in blister fluid were not pre-
mucus was less than 4% of that in serum and, there- dictive of the kinetics in synovial fluid as rate con-
fore, ibuprofen is not concentrated in this secre- stants of kinetic transfer into or out of each fluid
tion.[163] often did not parallel each other. It has been sug-
In patients with nerve-root compression pain gested that blister fluid is not a good model for
requiring a lumbar puncture the plasma and cere- predicting the kinetics of the enantiomers in syno-
brospinal fluid (CSF) concentrations of ibuprofen vial fluid in individual patients.[254] These studies
enantiomers have been determined. Both en- reflect a non-inflammatory model and results may
antiomers peaked later in the CSF (3 hours) than differ when inflammation is present. In addition,
130 Davies
studies that assess the unbound concentrations in strates for the epimerase. S-(+)-Ibuprofen is not
blister fluid should be undertaken to better charac- activated to the adenylate derivative and thus is
terise relative distribution of ibuprofen. not able to form a CoA thioester. Thus R-(–)-
The tissue kinetics of ibuprofen after topical ibuprofen CoA is epimerised and with sub-
application demonstrated high ibuprofen concen- sequent hydrolase activity R-(–) and S-(+) en-
trations within the therapeutic range to inhibit antiomers are released.[228,265-273] Equilibrium
prostaglandins in subcutaneous tissue, tendon, between glucuronide formation and elimination
muscles and joint capsule without systemic distri- is a major determinant of the S/R ratio, since these
bution.[58,196,258] One study suggests that after top- metabolic steps have been shown to be stereo-
ical application ibuprofen is stored in subcutaneous selective for ibuprofen.
fatty tissue and is subsequently released via syno- There have been 3 approaches used to estimate
vial fluid membrane into the synovial fluid of the
the extent of chiral inversion of ibuprofen. The first
treated knee joint.[259] Other studies have demon-
2 approaches are based on the estimation of clear-
strated specific binding of ibuprofen to muscle tis-
ance of S-(+)-ibuprofen using either stable isotope
sues compared with subcutaneous tissue.[260] In
vitro binding to various tissue components demon- methodology or the separate administration of S-
strates specific binding, especially to laminin and (+)-ibuprofen requiring multiple study periods. A
collagen type IV, which may explain higher con- third approach is based on the stereochemical com-
centrations in connective tissue compared with fat position of urinary metabolites by stereospecific
and surrounding tissues after topical applica- chromatography. Estimates of inversion did not
tion.[261] differ significantly between the administration of
Tissue distribution after a fatal overdose of racemic or R-(–)-ibuprofen.[274] The fractional in-
ibuprofen and paracetamol (acetaminophen) re- version of ibuprofen was significantly greater us-
ported post mortem serum and tissue concentra- ing the stereochemical composition of urinary me-
tions of 80.8 mg/L (serum), 238 μg/g (liver), 622.0 tabolites (63%) versus the method using clearance
μg/g (kidney) and 81.7μg/g (lung). Tissue concen- of deuterated S-(+)-ibuprofen (51%) after a dose of
trations of hydroxy ibuprofen were 43.0 mg/L (se- the racemate.[274]
rum), 115 μg/g (liver), 160 μg/g (kidney) and 56.7 It has been reported that R-(–)-ibuprofen is in-
μg/g (lung). Tissue concentrations of carboxy verted 52%,[194] 59%,[190] 60%,[193] 63%,[185]
ibuprofen were 101 mg/L (serum), 225 μg/g (liver), 65%,[200] 69%,[206] 69%,[229] an average of between
385 μg/g (kidney) and 432 μg/g (lung).[262] Tissue 53 and 65% in humans.[233] In calculating the per-
concentrations after ibuprofen fatal overdose were centage of inversion equal doses of each enantio-
518.0 and 348.3 mg/L in heart and femoral blood, mer are usually given individually and the AUC
942.1 μg/g in the liver, 283.9 μg/g in the brain and of the S-(+)-enantiomer derived from the R-(–)-
131mg total in gastric contents.[97]
enantiomer is compared with the AUC of the
R-(–)-enantiomer. However, this analytical ap-
2.5 Metabolism
proach assumes pharmacokinetic linearity and no
Ibuprofen undergoes extensive enantiomeric pharmacokinetic interactions between enantiomers.
inversion in humans and this metabolic process The pharmacokinetics of racemic ibuprofen due to
has been the subject of several excellent re- saturation of protein binding are non-linear at
views.[263,264] The inversion apparently proceeds higher doses.[99,125,206,224,243] Furthermore, larger
via stereoselective enzymatic activation of R-(–)- AUC values have been observed for the enantiomers
ibuprofen to R-(–)-ibuprofenyl-adenylate followed when given alone as compared with the race-
by an acyl coenzyme A(CoA) thioester formation mate.[185] These factors can both contribute to an
by an acyl CoA synthetase. The thioesters are sub- overestimation of the extent of inversion.
Glucuronic acid conjugate Glucuronic acid conjugate
CH 3 OH COOH† CH 3 COOH†
♦ ♦
C CH C C CH 2 C
H H OH H
CH 3 CH 3 CH 3 CH 3
1-Hydroxy ibuprofen 2-Hydroxy ibuprofen
CH 3 †
♦ COOH
C CH2 C
H H
CH 3 CH 3
(+/–) Ibuprofen Glucuronic acid conjugate
CH 3 † †
♦ COOH H ♦ ♦ COOH
C CH2 C C CH2 C
CH2 OH H CH 3 COO H
CH 3 CH 3 CH 3
3-Hydroxy ibuprofen Carboxy ibuprofen
Glucuronic acid conjugate Glucuronic acid conjugate

Fig. 1. Biotransformation of ibuprofen. Symbols: ◆ = chiral centre(s); † = sites of glucurondation.
The fractional inversion of R-(–)-ibuprofen has 1-Hydroxy ibuprofen and 3-hydroxy ibuprofen
also been determined by 2 methods (the stable iso- have also been found in urine in very small con-
tope method and the stereochemical composition centrations.[80,105] Cytochrome P450 (CYP) 2C9
of the urinary metabolites). Both give similar esti- has been identified as the most important catalyst
mates of inversion for oral administration between for formation of all the oxidative metabolites of
56 and 60%, respectively.[201] When R-(–)-ibu- R-(–) and S-(+)-ibuprofen.[275] The hydroxy and
profen was incubated in the presence of excised
carboxy metabolites have no apparent pharmaco-
human ileum and colon obtained from 3 cancer
logical activity.[216]
patients, chiral inversion as well as acylglucuron-
Recent evidence[276] suggests that CYP2C9 is
idation was evident in all segments, indicating that
the major CYP mediating the 2 and 3-hydroxyla-
the gut has the enzymes necessary for pre-systemic
metabolic inversion to occur.[197] tions of R- and S-ibuprofen in the liver of Cauca-
Ibuprofen is extensively metabolised via forma- sians. Other CYPs, particularly CYP2C8, may also
tion of the major metabolites 2-[4-(2-hydroxy-2- play a role in these biotransformations and hence
methylpropyl)phenyl] propionic acid (2-hydroxy the relative expression of CYP2C9 and 2C8 may
ibuprofen) and 2-[3-(2-carboxypropyl)phenyl] contribute to variability in the clearance of ibupro-
propionic acid (carboxy ibuprofen) [see fig. 1].[115] fen enantiomers.
132 Davies
A major metabolic pathway of ibuprofen is as the hydroxy and carboxy metabolites, respec-
conjugation with glucuronic acid to yield acyl tively, as a mixture of conjugated and unconjugated
glucuronides. Ibuprofen is also metabolised to forms.[248] Using immobilised (uridine diphosph-
ibuprofen acylglucuronide. The plasma concen- ate α-D-glucuronic acid) UDP glucuronyltrans-
trations of glucuronide in the elderly are 4% of ferases obtained from human livers the enantio-
that of the parent drug. Covalent binding of the selectivity of the glucuronidation of ibuprofen was
ibuprofen glucuronide to plasma protein was ob- studied. The results demonstrate that the stereo-
served which is believed to be important cause selectivity in glucuronidation. S-(+)-Ibuprofen was
of toxicity and anaphylactic reactions.[277] preferentially conjugated. The S/R ratio of the
Through direct coupling HPLC with nuclear diastereomeric isomers was 1.67 in human liver
magnetic resonance (NMR), the glucuronides of preparations.[283]
ibuprofen and 2-hydroxy ibuprofen have been Another metabolite, 2,4-carboxyphenylpropio-
identified to be β-1-O-acyl glucuronides.[278-280] nic acid, has also been identified in the dialysis
More recently 2-hydroxy ibuprofen, carboxy ibu- fluid of a nephrectomised patient.[284] Following
profen and 3-hydroxy ibuprofen, as well as the administration of a single oral dose of 400mg of
glucuronic acid conjugates of ibuprofen, 1-hydroxy racemic ibuprofen, a novel ibuprofen-taurine me-
ibuprofen, 2-hydroxy ibuprofen, 3-hydroxy ibupro- tabolite was isolated from urine requiring prior for-
fen and carboxy ibuprofen, were isolated by pre- mation of ibuprofen CoA thioester. This metabolite
parative solid phase extraction followed prepar- represents ≈1.5% of the dose and is 87% in the
ative HPLC, demonstrating that all the known S-(+) configuration. Separate experiments with
ibuprofen administered as a pseudo racemate mix-
phase I metabolites of ibuprofen form β-1-O-
ture of R-(–)-ibuprofen/S-[2-3H]-ibuprofen] the
acyl glucuronides at the carboxylic acid group of
majority of S-(+)-ibuprofen-taurine was derived
the propionic side chain.[281]
from S-(+)-ibuprofen, rather than from R-(–)-
The hydroxylated metabolites have 1 asymmet-
ibuprofen by way of chiral inversion. These find-
ric centre and exist as a pair of enantiomers. The
ings suggest that S-(+)-ibuprofen also participates
carboxylated metabolite has 2 asymmetric centres
in CoA dependent reactions, including metabolic
and, therefore, 4 stereoisomeric products are pos-
chiral inversion.[285] The participation of S-(+)-
sible (i.e. RS, SR, SS and RR configurations). There
ibuprofen in CoA dependent reactions can be also
are considerable problems in the analysis of car- appreciated after its chiral inversion observed in
boxy ibuprofen diastereoisomers and the RR/SR some species.[286,287]
diastereoisomers cannot be readily separated.
However, a recent report has demonstrated chro-
2.6 Elimination
matographic resolution of the 4 stereoisomers of
carboxy ibuprofen using a Chiralpak AD chiral sta- 2.6.1 Excretion in the Urine
tionary phase.[282] After administration of 800mg The excretion of drug and metabolites occurs
of racemic, R-(–) or S-(+)-ibuprofen, 71, 54 and rapidly in both urine and faeces. In 3 patients with
97% of the free hydroxy-metabolite was excreted rheumatoid arthritis receiving ibuprofen 600mg
in urine in the S-(+)-configuration; 71, 80 and 95% daily for 5 weeks, 44% of the dose was excreted in
of the intact drug was in the S-(+) configuration. urine within 24 hours; 8% was excreted as hydroxy
Measurement of the carboxy-metabolite demon- buprofen and 28% as carboxy ibuprofen.[8] In 3
strated 43% SS, 44% RS + SR, 13% RR; 33% SS, males given an oral dose of ibuprofen 200mg, 25%
42% RS + SR, 25% RR; 51% SS, 47% RS + SR, 2% of the dose was excreted as hydroxy ibuprofen (free
RR.[227] and conjugated), 34% as carboxy ibuprofen (free
Following oral administration of ibuprofen, ap- and conjugated) and no unchanged ibuprofen could
proximately 80% of the dose is recovered in urine be detected.[8] In humans, urinary excretion was
initially reported to be ≈ 60% of the dose, no separately approximately 1.7% is excreted as R-(–)-
ibuprofen was detected either conjugated or un- ibuprofen, 6% as S-(+)-ibuprofen, 10% as R-(–)-
conjugated, hydroxy ibuprofen unconjugated was hydroxy ibuprofen, 16% as S-(+)-hydroxy ibupro-
≈9% and conjugated ≈16%; carboxy ibuprofen un- fen, 12% as R-(–)-R-(–)-carboxy ibuprofen and
conjugated was ≈16% and conjugated ≈19%.[115] 11% as S-(+)-S-(+)-carboxy ibuprofen and 15% as
Preliminary studies suggest that the hydroxy R-(–)-S-(+)/S-(+)-R-(–)-carboxy ibuprofen with
and carboxy metabolite from the urine of volun- approximately 70% of a dose of R-(–)-ibuprofen
teers who received racemic ibuprofen was dex- dose was recovered in urine as free (46%) or con-
trorotatory. [1] Subsequently, the metabolic fate jugated (27%) ibuprofen, hydroxy or carboxy
of the individual enantiomers has been investi- ibuprofen. In addition, there was no significant dif-
gated. The specific rotation of the unconjugated ference in the metabolism of R-(–)-2H3-ibupro-
hydroxy and carboxy metabolites administration fen.[190]
of S-ibuprofen expressed as [α]D20 was +35.4 Total urinary recovery of ibuprofen and its met-
and +47.2, respectively. After administration of abolites was not significantly different between
R-(+)-ibuprofen the specific rotation was +2.8 intravenous (≈81%) and oral administration
and +7.2 for the hydroxy and carboxy metabo- (≈87%).[201] In humans, the total fraction of ibupro-
lites, respectively. [153] S-(+), R-(–) and racemic fen eliminated in bile, including phase I metabo-
ibuprofen was sequentially given to 3 volunteers lites, was 0.82%. In urine, 9.55% ibuprofen and
with a 1-week washout period between doses. conjugates, and 40.86% phase I metabolites were
After administration of S-(+)-ibuprofen the uri- recovered.[288]
nary products were exclusively dextrorotatory. Urinary recoveries of ibuprofen, hydroxy
The urinary excretion of the metabolites re- ibuprofen and carboxy ibuprofen between doses of
vealed that R-(–)-ibuprofen is inverted to S-(+)- 100 to 1200mg demonstrated no significant change
ibuprofen with 80% of the urinary products as with dose. Total recovery was about 80%, which
S-(+)-ibuprofen and 20% as R-(–)-ibuprofen and was 45% carboxy ibuprofen, 25% hydroxy ibupro-
54% as S-(+)-hydroxy ibuprofen and 46% as R-(– fen and about 12% ibuprofen.[193] In patients with
)-hydroxy ibuprofen. After administration of the osteoarthritis, approximately 71% of the single
racemate 71% was S-(+)-ibuprofen, 30% was R- dose and 100% of a long term dose of ibuprofen
(–)-ibuprofen, 71% was S-(+)-hydroxy ibuprofen were recovered in urine as ibuprofen, hydroxy
and 29% was R-(–)-hydroxy ibuprofen.[228] ibuprofen or carboxy ibuprofen.[200] Renal clear-
Total recovery in urine of ibuprofen and its met- ance represents approximately 1% (0.05 L/h) of
abolites is between 70 to 90% of the administered total body clearance.[202]
dose after a 24-hour collection.[125,135,145,220,274] Oral racemic ibuprofen (800mg), R-(–)-ibupro-
In 15 healthy volunteers approximately 12% of fen (600mg) or S-(+)-ibuprofen (600mg) were ran-
the dose was recovered as conjugated ibuprofen, domly administered to 6 healthy individuals. Total
≈11% as the hydroxy metabolite, ≈15% as the con- urinary recovery, expressed as a percentage of
jugated hydroxy-metabolite, ≈30% as the carbo- the administered dose of hydroxy ibuprofen
xymetabolite, ≈12% as the conjugated carbo- (21.8%) and carboxy ibuprofen (36.4%) following
xymetabolite.[125] In 12 healthy volunteers 10 to the racemic dose. Following administration of R-
15% was eliminated as ibuprofen, 25 to 30% as (–)-ibuprofen there was a total recovery of hydroxy
hydroxy ibuprofen, 30 to 40% as carboxy ibupro- ibuprofen (21.7%) and carboxy ibuprofen (33.4%).
fen (free and conjugated).[145] In 8 healthy volun- When the dose of S-(+)-ibuprofen is considered,
teers ≈11% of the dose was excreted in ibuprofen, the total recovery was 28.3 and 43.3%, respec-
20% as hydroxy ibuprofen and 43% as carboxy tively. The recovery of carboxy, but not hydroxy,
ibuprofen.[220] When R-(–)-ibuprofen is administered metabolite was significantly greater for S-(+)-
134 Davies
ibuprofen relative to the others implying that sig- R-(–) and 7.9% S-(+)], 24.7% of the dose was re-
nificant substrate stereoselectivity exists for car- covered as total hydroxy-ibuprofen [i.e. 4.4% R-(–)
boxy ibuprofen formation.[289] and 20.3% S-(+)], and 40.8% of the dose was re-
The amount of S-(+)-hydroxyibuprofen in urine covered as total carboxy ibuprofen [i.e. 5.6% RR,
exceeded that of the R-(–)-isomer after all 17.2% SS and 18.0% RS + SR].[206]
ibuprofen doses. Following oral doses of racemate
2.6.2 Excretion in Breast Milk
and R-(–)-ibuprofen 79% and 63% of hydroxy Although the possibility of ibuprofen excretion
ibuprofen was excreted in urine in the S-(+)-con- into breast milk exists, given the high degree of
figuration. Substantial difference in the excretion plasma protein binding and the lower pH of breast
of SR and RS carboxy ibuprofen metabolites exists milk than that in plasma, low concentrations of
between the 3 treatment groups and a modest prod- ibuprofen are expected in breast milk. The maxi-
uct stereoselectivity was demonstrated between the mal possible infant exposure to ibuprofen via
RS and RR ratio between racemic and R-(–)- breast milk is likely to be minimal. The American
ibuprofen excretion in urine.[290] Academy of Paediatrics considers ibuprofen to be
Total urinary recoveries expressed as a percent- compatible with breastfeeding.[290] In a case report
age of the administered dose for ibuprofen glucu- of a lactating woman after 17 days of therapy with
ronide, hydroxy ibuprofen and carboxy ibuprofen twice daily doses of ibuprofen 400mg, the concen-
after the racemic dose are 9, 22 and 36%, and 9, 23, trations of ibuprofen and its metabolites reported
35% for the R-(–)-ibuprofen dose, respectively. in breast milk were negligible (<0.05 mg/L).[291] In
The total urinary recovery of ibuprofen and its me- 12 women with post-caesarean section pain, con-
tabolites after S-(+)-ibuprofen (82%) was signifi- centrations of ibuprofen in breast milk and serum
cantly greater than after R-(–)-ibuprofen (66%) and were determined after ingestion of ibuprofen
racemic doses (67%). In addition, the urinary re- 400mg every 6 hours for 24 hours. No measurable
covery of carboxy ibuprofen was significantly amounts of ibuprofen were found in the samples of
greater for S-(+)-ibuprofen relative to the R-(–)- breast milk.[292]
enantiomer or racemate.[274] In a recent study[293] using a more sensitive
No difference was found between the percent- HPLC assay with a lower detection limit of 2.5
age of the total dose recovered in the urine as R-(–)- μg/L, ibuprofen was detectable in breast milk.
or S-(+)-ibuprofen plus metabolites after adminis- Ibuprofen was found to be rapidly excreted in
tration of S-(+)-ibuprofen 80.2 ± 8.47 versus race- breast milk 30 minutes after oral intake of
mate 74.1 ± 14%. However, after administration of 400mg, the concentration of unresolved ibupro-
S-(+)-ibuprofen significantly more S-(+)-ibuprofen fen was determined to be 13 μg/L. A milk plasma
(primarily as conjugates) was found in urine than ratio of 1 : 126 was determined and the exposure
that found following administration of the race- of a suckling infant was calculated to be
mate (13.6 versus 10.2%) with ≈20% as hydroxyl- 0.0008% of the maternal dose.
ated and 45% as carboxylated metabolites.[288] In 2.6.3 Clearance
contrast, a statistically significant greater recovery Several investigators have found that R-(–)-
of S-(+)-ibuprofen as compared with the racemate ibuprofen is eliminated from plasma more rapidly
in healthy individuals has been reported.[274] This than S-(+)-ibuprofen following administration of
stereoselectivity in the glucuronidation of ibuprofen the racemate.[78,185] However, other investigators
is consistent with results of a hepatic microsomal have reported similar plasma t1⁄2β for both en-
study.[283] antiomers.[154,188] The t1⁄2β and clearance values of
Finally after oral administration of racemate the enantiomers administered separately were
600mg, 10.4% of the dose was recovered as total comparable to the racemate. The mean residence
(unchanged plus conjugated) ibuprofen [i.e. 2.5% time of S-(+)-ibuprofen after administration of R-
(–) and racemic ibuprofen was significantly longer 3. Implications of Pharmacokinetic

than after administration of the pure S-(+)-enantio- Properties for Therapeutic Use
mer.[194]
The apparent clearance based on total concen- 3.1 Rationale for Development of
trations increases with the dose. A statistically Stereochemically Pure S-Ibuprofen
significant dose-dependency of clearance for free
There remains considerable interest in under-
drug was also demonstrated but is of a lesser mag- standing the pharmacokinetic-pharmacodynamic
nitude. Free drug clearance increased 18% over a relationships of ibuprofen as recently demon-
dosage range of 400 to 1200mg versus 40% for strated by the international symposium ‘Update on
total ibuprofen.[235] A more recent study demon- S-(+)-ibuprofen’.[295,296] As the anti-inflammatory,
strates clearance of S-(+)-ibuprofen is greater than anti-thrombotic and analgesic effects of most
R-(–)-ibuprofen and likewise the unbound partial chiral NSAIDs have been attributed to the S-
clearances of S-(+)-ibuprofen was greater. The (+)-enantiomer, the R-(–)-enantiomer has been
half-life of unbound S-(+)-ibuprofen increased in considered by some investigators as a useless and
potentially harmful ingredient. However, for ibu-
a progressive and consistent manner as the percent-
profen the R-(–)-enantiomer also acts as a prodrug
age of R-(–)-ibuprofen increased in a variety of
because it is bio-inverted to S-(+)-ibuprofen. Sev-
dosage combinations.[206] eral investigators have expressed concerns about
There is considerable variability in the reported the toxicity of R-(–)-enantiomers. Stereospecific
values of metabolites found in urine in the litera- incorporation of R-(–)-ibuprofen into triglycerides
ture. Several deconjugating procedures, i.e. enzy- during the inversion process in the rat has been
matic hydrolysis, acidic hydrolysis and alkaline suggested to contribute to CNS adverse effects. [256]
hydrolysis, have been performed in these studies. Moreover, the 2-arylpropionyl-CoA epimerase has
Recently Hirai et al.[34] demonstrated that the 3 significant homology to enzymes involved in car-
methods of enzymatic hydrolysis used may have nitine metabolism.[297] However, no studies have
differential effects on the metabolite of interest yet been undertaken to investigate the pharmaco-
logical and/or toxicological consequences of hybrid
and the internal standard used in the assay. For
triglyceride formation.[298] In addition, a recent re-
ibuprofen, total values (free and conjugated) of port indicates that in the rat the R-(–)-enantiomer is
ibuprofen obtained by deconjugation were 50% also able to reduce renal function similar to its
higher in the acidic hydrolysis than they were in optical antipode.[299,300]
the enzymatic hydrolysis. This discrepancy may be Nevertheless, it has been suggested that by mar-
explained by labile ibuprofen acylglucuronide keting stereochemically pure S-NSAIDs, it may be
formed by intramolecular acyl migration to ibupro- possible to circumvent potential toxic effects as-
fen. Acyl glucuronide is resistant to β-glucuron- cribed to the ‘inactive’ R-enantiomer.[301] Indeed,
idase cleavage and may account for some of the the rationale behind the marketing of chiral drugs
literature discrepancies in metabolic data. Analysis and the therapeutic advantages of administering
chiral drugs as racemates has been questioned. It
of ibuprofen metabolites by semi-microcolumn
has also been suggested that as a prodrug the R-(–)-
liquid chromatography with ultraviolet absorp-
enantiomer may be a safer alternative to the avail-
tion and pulsed amperometric detectors has re- able racemate.[302]
cently been reported which may further help to The relative concentration of the S-(+)-enantio-
provide accurate information concerning the ex- mer of ibuprofen (S : R ratio) may increase with
tent of glucuronic acid conjugation in the analysis prolongation of the GI tract residence time of a
of ibuprofen metabolites.[294] racemic formulation postulated to be due to an
136 Davies
increase in chiral inversion of R-(–)- to S-(+)- The issue of marketing a racemate or a stereo-
ibuprofen within the GI tract.[197] Administration chemically pure drug must also be analysed from a
of S-(+)-ibuprofen would, therefore, reduce any pharmacological viewpoint. It is important to rec-
formulation-dependent variability in the concen- ognise that there are other cyclo-oxygenase-inde-
tration of the S-(+)-enantiomer within the body. pendent mechanisms of action of ibuprofen which
However, inter-individual variation in the pharmaco- may also enable anti-inflammatory actions. Both
kinetics of S-(+)-ibuprofen following administra- of the enantiomers and the racemate block calcium
tion of the racemate was similar to that following ionophore-induced leukotrienene B4 (LTB4) for-
the administration of the S-(+)-enantiomer, sug- mation with equal potency.[5] In addition, the an-
gesting that chiral inversion is not a major factor tagonistic action of ibuprofen on polymorphonu-
contributing to variability in the disposition of clear superoxide and β-glucuronidase release
ibuprofen.[302] However, the clearance of R- appears to be independent of its inhibitory effect
ibuprofen demonstrated a greater range of variabil- on cyclo-oxygenase, as R-(–)-ibuprofen was equiv-
ity than that of S-(+)-ibuprofen, which may reflect alent to the racemate.[5]
some variability in the inversion process.[302] Recent clinical data[309] have confirmed that S-
Enantiomers have identical physiochemical ibuprofen inhibits the activity of cyclo-oxygen-
properties in an achiral environment. However, ase-1 (COX-1) [concentration of drug inhibiting
physiochemically enantiomers may have very dif- activity by 50% (IC50 = 2.1 μmol/L)] and cyclo-
ferent water solubilities and faster dissolution rates oxygenase-2 (COX-2) [IC50 = 1.6 μmol/L] equally.
than their respective racemate. S-(+)-ibuprofen R-Ibuprofen inhibits COX-1 less potently (IC50 =
shows appreciably higher solubility, a lower melt- 34.9 μmol/L) than S-ibuprofen and demonstrates
ing temperature, higher dissolution rates and a dif- no inhibition of COX-2 up to 250 μmol/L. Con-
ferent crystal structure compared with the racemic versely, R-ibuprofenoyl-CoA thioester inhibition
form.[303] A formulation of S-(+)-ibuprofen, there- of COX-2 is greater than COX-1 (IC50 5.6 vs 219
fore, may have a more rapid absorption and physio- μmol/L). these data suggest a contribution of R-
logical availability which could produce a shorter ibuprofen to therapeutic effects not only via chiral
time for pharmacological effects to occur.[194,304] inversion to S-ibuprofen but also via inhibition of
With 1000 to 1500mg of S-(+)-ibuprofen, a COX-2 mediated by R-ibuprofenoyl-CoA thioes-
good symptomatic therapy of rheumatoid arthritis ter. These findings are consistent with racemic
is possible.[194] In a study of 24 patients with rheu- ibuprofen being one of the safest NSAID drugs
matoid arthritis S-ibuprofen demonstrated efficacy used clinically. However, in light of these findings
and duration of action similar to the racemate. It the toxicological consequences of R-ibuprofen ad-
was also suggested that the R-(–)-enantiomer in the ministration in comparison with the racemate or
form of the racemate does not have any therapeutic S-ibuprofen in situations of pre-existing inflamma-
effect.[305] S-(+)-ibuprofen (Garbo, Fieberbrunn, tion where COX-2 is expressed such as in gastric
Austria) has become available clinically in Austria ulcer and/or colitis may warrant further investiga-
since 1994. A post-marketing surveillance study in tion.
1400 patients demonstrated high effectiveness As many clinical adverse effects of NSAIDs re-
with a markedly low adverse event potential.[306] sult from their inhibition of prostaglandin forma-
S-(+)-Ibuprofen appears to be an effective analge- tion, the racemate or R-(–)-ibuprofen may be supe-
sic anti-rheumatic drug in the dose range of 1 to 1.5 rior to S-(+)-ibuprofen because it is less potent in
g/day.[194,307] However, an initial clinical endos- inhibiting prostaglandin formation but preserves
copy study suggest the gastric tolerability of S-(+)- antineutrophil activity. The inhibition of β-oxida-
ibuprofen is not significantly superior to that of tion of fatty acids by either ibuprofen enantiomer
racemic ibuprofen.[308] may lead to microvesicular steatosis.[310] In animal
models there was no difference between the en- conditions, the recommended dosages for ibupro-
antiomers of ibuprofen on the β-oxidation of pal- fen are 400 to 800mg 3 or 4 times daily.
mitate in the rat, suggesting this inhibition is A positive correlation has been demonstrated
primarily via a non-stereoselective non-coenzyme between total ibuprofen concentrations and anal-
A-dependent mechanism.[311] gesic effect in patients with mild to moderate pain
It is not known if R-(–)-ibuprofen affects febrile subsequent to third molar extraction.[314] The anal-
response. The site of temperature reduction by gesia response, as measured by the percentage sum
ibuprofen is likely within the brain. During the of pain intensity score differences, correlates sig-
inversion of the R-(–)-enantiomer, the lipophilic nificantly with the total serum concentrations of
R-(–)-ibuprofenyl-CoA may pass through the ibuprofen 1, 2 and 3 hours post-dose. The correla-
blood-brain barrier more easily than the S-(+)- tions were at their highest between serum concen-
ibuprofen and once in the brain may be converted trations and pain intensity difference values 1 hour
to the active S-(+)-ibuprofen. The 2-arylpropionyl- post-dose.[314] However, a follow-up study could
CoA epimerase mRNA and protein have been not demonstrate a significant correlation between
localised into the brain in animal studies.[296,312] In efficacy measures in post-operative patients after
such a case R-ibuprofen may contribute to tem- bilateral third molar surgery and various pharmaco-
perature-reducing, analgesic effects and anti- kinetic parameters.[184]
Alzheimer’s effects of the racemic administered Modification of the rate and extent of ibuprofen
ibuprofen, even if it itself is ‘inactive’.[169] absorption results in quicker absorption and signif-
icantly higher plasma concentrations in the first
3.2 Dose and Therapeutic Range hour following the oral administration of a solu-
ble ibuprofen formulation in patients with osteo-
Ibuprofen is available as an over-the-counter
medication throughout the world with the usual articular pain. Demonstrated pain intensity reduc-
recommended adult daily dosage of 200 to 400mg tion was significantly quicker and higher with a
every 6 hours. The dosage recommendation in pa- soluble granular form of ibuprofen compared with
tients with rheumatoid arthritis are a maximum of tablets.[166]
3200 mg/day. Ibuprofen has a wide therapeutic A recent study comparing the anti-nociception
window, between 10 to 50 mg/L, and a toxic con- produced by 2 oral formulations of ibuprofen
centrations of >100 mg/L. effervescent versus tablets demonstrated a dose-
It has been shown that high doses of ibuprofen related decrease in pain-related potential ampli-
taken consistently for 4 years result in total serum tudes.[214] In addition, maximum plasma concen-
concentrations of 50 to 100 mg/L and can decrease trations of ibuprofen were reached 15 to 40 minutes
pulmonary complications in patients with cystic after administration of the effervescent form, while
fibrosis over 5 years of age. Monitoring of the se- ibuprofen tablets had a tmax of 60 to 90 minutes.
rum concentrations is important in these pa- The results of this study support the hypothesis that
tients.[313] Emotional lability (defined as short tem- the antinociceptive effects of an NSAID is stronger
per, irritability, rebellious or aggressive behaviour) the faster it is absorbed. Superior and more consis-
and epistaxis could not be clearly associated with tent antinociceptive properties of the effervescent
AUC or Cmax in patients with cystic fibrosis.[159] form of ibuprofen were evident when compared
The t1⁄2β is short for ibuprofen (typically 2 with tablets.[214] There is some indication that
hours), necessitating frequent administration (up chemosomatosensory event-related potential la-
to 4 times daily) to maintain plasma concentrations tencies were prolonged with the effervescent dos-
within the therapeutic range. A less frequent ad- age form.
ministration regimen may be established using a A pharmacokinetic-pharmacodynamic model
sustained release formulation. In inflammatory for the analgesic effect of ibuprofen using subjec-
138 Davies
tive, as well as objective, parameters has been de- tionship between anti-pyretic response and plasma
veloped.[215] The pharmacokinetic data of S-(+)- concentration was examined in children using ef-
ibuprofen was linked to the effect data using a hy- fect compartment modelling. There was a temporal
pothetical effect compartment. The effect data lag of 1 to 3 hours between ibuprofen Cmax and
could be fitted to an maximum effect (Emax) model. peak temperature decrement. The mean slope of the
There was an evident time lag between Cmax and effect compartment concentration versus tempera-
the decrease in evoked potentials. The relationship ture regression was –0.242°C per mg/L.[168] An
between evoked potential and S-(+)-ibuprofen se- anti-clockwise hysteresis was evident upon plot-
rum concentration was, therefore, examined using ting of total, R-(–) or S-(+)-ibuprofen plasma con-
effect compartment modelling. There was a tempo- centration versus mean temperature difference and
ral lag of 30 minutes to 1 hour between peak joining the points in temporal order.[168] Interest-
ibuprofen serum concentration and the decrease in ingly, in younger children the onset of anti-pyresis
evoked potential. An anti-clockwise hysteresis was earlier (69 vs 109 minutes in older children)
loop was evident upon plotting of S-(+)-ibuprofen and the maximum anti-pyretic effect was greater
serum concentration versus the percentage de- (2.8°C vs 1.8°C). It is postulated that the greater
crease in evoked potential. Using effect-compart- relative body surface area in younger children may
ment modelling, the hysteresis loop was collapsed allow more efficient dissipation of heat in response
and a linear relationship between S-(+)-ibuprofen to anti-pyretic-induced lowering of the tempera-
serum concentration and analgesic effect was ture set point in the hypothalamus.
evident. Conversely, it has been reported that in patients
The concentration of the drug which produced with burns the serum concentrations of ibuprofen
50% of Emax (EC50) of ibuprofen and evoked po- did not correlate with maximum temperature dec-
tential was 8.71 ± 3.67 mg/L and for pain rating rement.[172] Pharmacodynamic modelling of the
24.4 ± 1.2 mg/L. The pain rating data demonstrated anti-pyretic effect of ibuprofen has also been char-
considerable variability and further studies are on- acterised using models of indirect pharmaco-
going to clarify these differences.[215] dynamic response with reasonable estimates of the
In addition, a significant correlation between IC50 of 10.1 mg/L.[319]
clinical efficacy, as assessed by articular index in Patients with dysmenorrhoea treated with
patients with rheumatoid arthritis, and total serum ibuprofen 400mg demonstrated a maximum serum
ibuprofen has been demonstrated.[315-317] Further- concentration after 1 hour and a marked reduction
more, S-(+)-ibuprofen AUC correlated with im- in intra-uterine pressure and severity of pain was
provement in disability, rest pain and with the phy- recorded 1.5 hours following the administration of
sicians’ global assessment of the severity of ibuprofen. Despite a low or non-detectable serum
arthritis in 45 patients with hip or knee osteoarthri- concentration of ibuprofen 4 hours following ad-
tis treated with a single doses of ibuprofen for 4 ministration, intra-uterine pressure never regained
weeks.[317] The average and trough concentrations its pretreatment level. Such an observation may be
of S-(+)-ibuprofen also correlated with the im- indicative of a significant contribution of the frac-
provement in disability; trough concentrations also tion excreted into the myometrium sufficient to
correlated with physicians’ global assessment. In- maintain reduced muscle activity.[320]
terestingly, when total (R + S) was substituted for No clinical studies have reported a correlation
S-(+)-ibuprofen these variables demonstrated a between the toxicity and plasma concentrations of
similar correlation. ibuprofen. However, animal studies indicate that
There was an evident time lag between Cmax and the ulcerogenic activity of ibuprofen is systemic
peak anti-pyretic response in febrile children aged and related to the plasma concentration of the
between 0.25 and 12 years old.[165,169,318] The rela- drug.[216]
A blood concentration nomogram (Poisondex®) insufficiency compared with 1.07% in the control
was developed to predict patients at risk for serious group.
adverse effects (>100 mg/L) from ibuprofen toxic- After correcting for protein binding the Vd of
ity.[321] However, studies suggest that a poor corre- unbound ibuprofen was significantly lower in renal
lation between concentration and outcome limits failure compared with controls and peak serum
practical usefulness of this nomogram.[322,323] It is concentrations of unbound ibuprofen were signif-
not known if stereospecific measurement and icantly higher. In addition, free clearance of
measurement of unbound concentrations of ibupro- ibuprofen in patients was lower than that in con-
fen could improve the usefulness and predictability trols although this did not reach statistical signifi-
of concentration-effect relationships. cance in this small sample number.[134]
Haemodialysis is utilised as a therapeutic sup-
3.3 Disease and the Pharmacokinetics portive treatment for end-stage renal disease. In an
of Ibuprofen initial study patients with uraemia appeared to ab-
sorb ibuprofen at a slower rate as compared with
Burn injury can alter the pharmacokinetics and healthy individuals. Furthermore, considerably
pharmacodynamics of xenobiotics.[234] Ten pa- lower plasma concentrations compared with val-
tients with serious burns were studied after the ad-
ues in healthy patients were evident. The haemo-
ministration of 10 mg/kg ibuprofen suspension.
dialysis system yielded a mean extraction effi-
Burn size did not alter the half-life or AUC of
ciency of 16.7% for ibuprofen, drug recovery
ibuprofen, however, the maximum ibuprofen con-
resulting from haemodialysis represented a small
centration varied greatly, depending on the route
fraction of the ingested dose of ibuprofen (<4%)
of administration 1 week after burn injury (table
and t1⁄2β was not significantly affected. The fraction
IV). Administration of ibuprofen directly into the
of unbound ibuprofen in uraemic plasma was of a
small bowel via a transpyloric tube produced a
higher order (10%) compared with healthy individ-
plasma concentration versus time curve similar to
intravenous administration with rapid absorption uals (≈4.8%) and could lead to an increased Vd in
and a high Cmax. Conversely, intragastric adminis- uraemia.[36] The metabolite concentrations were
tration produced a lower Cmax which occurred not evaluated in these patients.
several hours later. The percentage of the body sur- The elimination kinetics of ibuprofen were sub-
face area burned did not correlate with drug ab- sequently studied in patients with renal failure un-
sorption.[172] dergoing haemodialysis treatment and it was dem-
The elimination of ibuprofen may be dependent onstrated that plasma concentrations of ibuprofen
upon urinary excretion of conjugated metabolites, were not affected by the haemodialysis. However,
which may be influenced by reduced renal func- the hydroxy and carboxy metabolites of ibuprofen
tion. The pharmacokinetics of ibuprofen in pa- accumulated significantly and were both detected
tients with chronic renal insufficiency receiving in the dialysate.[137]
haemodialysis administered single doses of Most patients with renal insufficiency show el-
ibuprofen showed lower total ibuprofen serum evated plasma S-(+)-ibuprofen concentrations,
concentrations compared with the control group. higher AUC for S-(+)-ibuprofen and increased
The apparent volume of distribution (Vd) and oral AUC S : R ibuprofen ratios compared with healthy
clearance of ibuprofen were higher in patients with individuals. A reduced clearance of S-(+)-
renal failure although these differences did not ibuprofen occurs with reduced renal function.[205]
reach statistical significance compared with con- In addition, a diminished unbound clearance of S-
trols. Ibuprofen was less extensively bound to se- (+)-ibuprofen in renally impaired individuals re-
rum protein in patients with renal failure. The mean sults in a 45% higher unbound S-(+)-ibuprofen
free fraction was 3.08% in patients with renal steady-state concentration.[277] Patients with cardio-
140 Davies
vascular disorders (i.e. hypertension, hyperlipid- higher in patients with cirrhosis (1.1 vs 0.79) sug-
aemia, congestive heart failure, etc.) may have un- gesting an impairment of metabolic inversion.
stable renal haemodynamics. An elevated S-(+)- The administration of the S-(+)-enantiomer to
ibuprofen AUC and higher S : R AUC ratio patients with cirrhosis showed impairment of the
occurred in these patients. Two independent risk t1⁄2β (1.6 vs 2.6 hours) and an increase in AUC (101
factors, namely advanced age and hypertension, vs 144 mg/L • h).[203] A subsequent study compar-
contribute to increased S-ibuprofen AUC in this ing patients with liver cirrhosis and healthy indi-
population. Half-life was independent of most dis- viduals demonstrated higher AUC values for R-(–)-
ease states except for diabetes mellitus and hyper- and S-(+)-ibuprofen (+37% and 27%, respectively)
tension, which prolonged the t1⁄2β of S-(+)-ibupro- and longer t1⁄2β [+40% R-(–) and + 44% S-(+)]. A
fen.[209] mean ratio AUC S-(+)/AUC R-(–) was lower in pa-
The toxicological relevance of the pharmaco- tients than in healthy individuals suggesting an im-
kinetic data may result in patients with asymptom- pairment of inversion from R-(–) to S-(+) and an
atic renal failure progressing to acute renal fail- impairment of elimination in patients with cirrho-
ure.[324] Ibuprofen decreased creatinine and 3-hour sis.[94]
inulin clearance after single doses of ibuprofen The use of ibuprofen in patients with haemo-
800mg in elderly patients with and without renal philia for chronic haemophilic arthropathy is asso-
insufficiency. In patients with renal insufficiency, ciated with transient coagulation abnormalities.
creatinine clearance did not change after 1 month Patients with haemophilia treated with ibuprofen
and zidovudine demonstrate excess bleeding and
of ibuprofen administration.[325]
lowered platelet adhesiveness. However, the ten-
The functional capabilities of the liver may
dency to bleed was unrelated to the Cmax of ibupro-
influence drug metabolism and, therefore, liver
fen or zidovudine. The clearance of ibuprofen
disease may alter the pharmacokinetics of xeno-
alone and zidovudine alone were not significantly
biotics. It was initially reported that patients with
different from the clearance of both drugs admin-
liver cirrhosis had longer half-lives (1.85 versus
istered concomitantly.[171]
1.45 hours) than healthy individuals. The AUC in
The pharmacokinetics of ibuprofen in children
patients with cirrhosis was significantly greater with cystic fibrosis receiving ibuprofen 13.4 mg/kg
than in controls, which was postulated to be be- was compared with those in 4 healthy children who
cause of a 52% increase in bioavailability. [326] received a similar dose. The Cmax was decreased by
Even though ibuprofen is eliminated by oxida- 27%, the AUC was decreased by 46%, apparent
tive metabolism the effect of alcoholic liver disease total clearance was increased by 77% and apparent
on the pharmacokinetics of ibuprofen was demon- Vd was increased by 84% in the children with cys-
strated to be minimal. The absorption of ibuprofen tic fibrosis; the tmax and t1⁄2β were not significantly
appeared to be delayed in some patients with poor different.[313] The pharmacokinetic mechanism(s)
hepatic function and slight differences were noted responsible for these changes may involve de-
in serum AUC and terminal elimination rate.[124] creased protein binding or increased hepatic meta-
Following a single racemic dose of oral ibuprofen bolism. In addition, the extent of absorption is not
600mg, the stereoselective disposition was studied known for patients with cystic fibrosis, which
in 8 patients with moderate to severe cirrhosis. could affect apparent clearance estimations.
Half-life was significantly prolonged and lower Administration of S-ibuprofen to 6 patients with
amounts of ibuprofen were excreted as conjugates rheumatism demonstrated that the pharmaco-
in urine [6.4 vs 26.5% S-(+)-ibuprofen) and 0.9 vs kinetic disposition were similar to that in healthy
4.1% R-(–)-ibuprofen] compared with healthy in- volunteers.[194] A study in patients with osteoarthri-
dividuals. The AUC ratio R : S was significantly tis examined both the inter- and intra-individual
variability in the disposition of ibuprofen follow- and/or a higher clearance of the S-(+) enantiomer.
ing administration of the racemate. The clearance No relationship was evident for the S/R ratio and
of R-(–)-ibuprofen demonstrated a greater variabil- tmax suggesting a lack of pre-systemic gut inver-
ity and the range of values and pharmacokinetic sion.
parameters were in good agreement with healthy In addition, lower urinary recovery of conju-
individuals in previous studies.[200] gated drug in infants (≈3.5%) compared with
Obese individuals had significantly lower adults (≈9%) was evident. This difference has been
ibuprofen Cmax than non-obese individuals. The attributed to either immature glucuronidation, a
Vd for ibuprofen was increased in obese individu- lower bioavailability, or to an increased formation
als; however, the Vd corrected for bodyweight was clearance of ibuprofen to other metabolites. How-
decreased in obese individuals, indicating that ever, these differences did not reach statistical
ibuprofen distribution into bodyweight in excess significance.[176]
of the ideal bodyweight is less extensive than its Interestingly, the relative proportion of ibupro-
distribution into ideal bodyweight. The clearance fen in synovial fluid in children seems to be
of ibuprofen was also increased in obese individu- slightly higher after repeated doses than in adults
als.[132] after a single dose. In adults, the Cmax of ibuprofen
in synovial fluid is one-third of that in serum,[251]
3.4 Influence of Age on the whereas in children the Cmax in synovial fluid was
Pharmacokinetics of Ibuprofen about 40% of the maximal concentrations in se-
rum.[118]
3.4.1 Children Recently, the pharmacokinetics and protein
In general, therapeutic regimens in paediatric binding of intravenous ibuprofen in the newborn
patients are based on the extrapolation of pharma- infant have been reported in the prevention of
cokinetic data from adults. The pharmacokinetics intraventricular haemorrhage and closure of patent
of ibuprofen are not affected by dose between 5 and ductus arteriosus.[183] Gestational age and birth-
10 mg/kg or age between 3 and 10 years old.[160] weight were not related to drug elimination. Pro-
The effect of age on ibuprofen pharmacokinetics tein binding demonstrated that the percentage of
in infants and children aged 3 months to 10.4 years bound ibuprofen was significantly lower in full
demonstrated that age did not significantly influ- term cord plasma 94.8% compared with the adult
ence the rate of absorption, plasma concentration plasma 98.73%.[327] The effect of ibuprofen on bi-
or elimination.[168] No age-related differences in lirubin-albumin binding in adult and newborn in-
absorption or t1⁄2β of ibuprofen were observed but fant serum at clinically appropriate ibuprofen con-
children <2.5 years had a greater clearance of centrations demonstrates that the free fraction of
ibuprofen than did children >2.5 years of age, bilirubin is increased by a factor of 4.[151] In addi-
primarily because of the increase in Vd. [165] tion, compared with data from adults and older
In febrile children, stereoselective pharmaco- children, ibuprofen elimination is markedly pro-
kinetics had an appearance consistent with those longed in neonates and protein binding is slightly
previously demonstrated in adults.[312] The differ- lower.[327] Caution should be exercised when
ential pharmacokinetics of the individual en- ibuprofen is used in sick premature infants as the
antiomers has been studied in children following a risk of bilirubin encephalopathy and other toxico-
single oral dose of the racemate for post-operative logical manifestations may be increased.
analgesia. Plasma concentrations of the S-(+)-
enantiomer were lower than those reported in 3.4.2 Elderly Patients
adults, suggesting a higher dosage might be re- The pharmacokinetics of a single dose of
quired in infants.[176] These differences may sug- ibuprofen 600mg were studied in healthy male and
gest impaired R-(–) to S-(+) inversion in the infant female volunteers, aged 22 to 44 and 60 to 88 years.
142 Davies
Similar tmax and Cmax values were determined in the younger group.[233] The pharmacokinetics of
each group. In elderly compared with young males S-(+)-ibuprofen are significantly different in el-
the t1⁄2β of ibuprofen was significantly longer (2.4 derly patients with renal impairment compared to
vs 1.5 hours). Moreover, the elderly men demon- healthy elderly volunteers: the t1⁄2β was increased,
strated a larger Vd than that found in young men the unbound clearance was decreased and the un-
(14.1L vs 11.61L), however, these differences were bound concentration at steady state was increased,
not significant when corrected for bodyweight. In unbound clearance, glucuronidation and hydroxyl-
addition, elderly men demonstrated significantly ation were reduced in elderly patients with renal
lower clearance than young men (0.0576 vs 0.0618 impairment.[233]
L/h • kg). The free fraction of ibuprofen in plasma
did not appear to be affected by age nor was there 4. Pharmacokinetic Drug Interactions
apparent differences in the pharmacokinetics be-
tween young and elderly females.[131] 4.1 Effect of Other Drugs on the
Another study in elderly (65 to 78 years old) Pharmacokinetics of Ibuprofen
compared with younger males (22 to 35 years old)
There is sparse information regarding the ef-
did not demonstrate any statistically significant
fects of other drugs on the pharmacokinetics of
differences in any pharmacokinetic parameter
ibuprofen. Aspirin (acetylsalicylic acid), when ad-
studied. This suggests that advanced age has only
ministered concurrently, significantly affects the
a minimal influence on the pharmacokinetics of
pharmacokinetics of ibuprofen, producing a signif-
ibuprofen and that no dose adjustment is neces-
icant and pronounced lowering of serum ibuprofen
sary.[129] Elderly patients with rheumatoid arthri-
concentrations without effecting the t1⁄2β of the
tis[57,60,63,67,69,89,91-96,98-102] also demonstrate no
drug.[235,316] In patients with rheumatoid arthritis
clinically significant deviations in pharmacokinet-
there was no additive effect between low dose com-
ics compared with younger patients.[151] bination of aspirin 2.4g and ibuprofen 800mg daily
A pharmacokinetic comparison of ibuprofen and a weak additive effect between the high dose
sustained release tablets given to younger (19 to 60 combination (ibuprofen 1600mg and aspirin 3.6g)
years old) and elderly (65 to 85 years old) patients daily.[316] This may be relevant because of the po-
for 2 weeks demonstrates comparable pharmaco- tential for self-administration of aspirin by patients
kinetics without appreciable drug accumulation.[157] already receiving ibuprofen. The mechanism for
A more recent stereoselective study suggests age- this pharmacokinetic interaction involves a dou-
related pharmacokinetic changes. In a study of 18 bling of the unbound ibuprofen fraction by high
healthy volunteers of different age groups (20 to 34 concentrations of salicylates. It appears that dis-
versus 44 to 63-year-old groups), the older group placement of ibuprofen from protein binding by
showed a reduced ibuprofen clearance with ele- salicylate contributes to the pharmacokinetic inter-
vated t1⁄2β R, AUC R-(–), and AUC S-(+), as well as action between the 2 drugs in vivo.[32,328] A low
a reduced clearance/fraction of absorption of the R total ibuprofen synovial fluid to serum ratio was
isomer. The S : R AUC ratio was 1.8 for the youn- apparent for 3 patients with rheumatoid arthritis on
ger group and 1.44 for the older group, suggesting concomitant aspirin therapy, consistent with an as-
a correlation between S-(+)-ibuprofen accumula- pirin-salicylate interaction.[252]
tion and age.[208] When paracetamol is administered concurrently
A follow-up study in young healthy volunteers, in healthy adults there were no significant differ-
healthy elderly volunteers and elderly patients with ences in ibuprofen pharmacokinetics.[127]
creatinine clearance between 1.8 and 4.2 L/h dem- Antacids and H2-antagonists are sometimes co-
onstrated both elderly groups had significantly de- administered with NSAIDs as gastroprotective
creased binding of S-(+)-ibuprofen compared with agents to treat the gastric and duodenal ulcers
caused by this class of drugs. Pretreatment with White volunteers.[330] The potential interaction
cimetidine for a week did not significantly effect between cimetidine and ibuprofen has sub-
the total serum disposition pharmacokinetics of sequently been assessed using a stereospecific as-
ibuprofen.[329] Compared with ibuprofen adminis- say.[189] There were no pharmacokinetic differ-
tered alone, cimetidine increased the peak serum ences between ibuprofen administered alone or
ibuprofen concentration (64 vs 56 mg/L) but with cimetidine. In addition, the percentage of un-
ranitidine treatment values were indistinguishable bound ibuprofen did not differ between the treat-
from ibuprofen alone.[323] The impairment of ment groups nor did the percentage of adminis-
ibuprofen clearance by cimetidine was small and tered dose or the metabolite profile recovered in
ranitidine had no significant effect on ibuprofen urine differ.[189]
clearance.[323] No significant pharmacokinetic differences were
A follow-up study was undertaken assessing the detected after misoprostol or ranitidine coadmin-
possibility of a stereochemical interaction between istered with ibuprofen.[164] In another study of 18
ibuprofen and cimetidine. Cimetidine caused a sig- volunteers who received ibuprofen 800mg with
nificant increase in the Cmax of both the ibuprofen misoprostol, no significant differences in either the
enantiomers, R-(–)-ibuprofen being elevated by misoprostol or ibuprofen concentrations were
28% and S-(+)-ibuprofen by 23%. The AUC in- demonstrated whether given individually versus
creased 37% for R-(–)-ibuprofen and 19% for S- concomitantly.[331] A recent study has investigated
(+)-ibuprofen although this did not reach statistical a possible analgesic interaction of misoprostol
significance nor did the t1⁄2β or urinary metabolites with ibuprofen. Both ibuprofen 200mg alone and
differ.[191] The potential interaction between ibuprofen 200mg and misoprostol 200μg demon-
ibuprofen and nizatidine and cimetidine demonstrated analgesic effectiveness but were not differ-
strated no differences in AUC, rate of absorption ent from each other. The combination group had
or t1⁄2β of ibuprofen. [146] The effect of elevating higher ibuprofen blood concentrations during the
gastric pH through the use of ranitidine on the re- first 45 minutes but had a lower Cmax and a longer
lease characteristics of a single sustained release tmax.[211]
ibuprofen tablet demonstrated that the release of The effect of aluminum and magnesium hydr-
ibuprofen was unaffected by elevation in gastric oxide suspension on the pharmacokinetics of
pH as evident by the similarity of serum concen- ibuprofen in healthy volunteers demonstrated no
trations and urinary excretion data after the 2 treat- significant differences between treatment groups.[142]
ments.[147] Single doses of magnesium hydroxide immedi-
A study was undertaken to determine whether ately after ibuprofen ingestion increased AUC be-
ranitidine or cimetidine affects the pharmaco- tween 0 to 1 hour by 65% and the ibuprofen Cmax
kinetics of ibuprofen at steady-state conditions. by 31% with a shorter tmax at about 30 minutes. The
There were no significant differences in pharmaco- increased solubility of ibuprofen at high pH may
kinetics.[149] A re-analysis of the Stephenson et explain the effect of magnesium hydroxide on ab-
al.[149] study looked at the question of steady-state sorption rate. However, the extent of bioavailabil-
differences between gender and racial groups. Dif- ity of ibuprofen was not increased by magnesium
ferences between Black and White volunteers were hydroxide.[161]
significant when the effect of ranitidine or cimeti- Compared with ibuprofen administered alone
dine administration on Cmax was analysed. Admin- an an initial study demonstrated that the AUC de-
istration of ranitidine and cimetidine was associ- creased by 11.8%, mean Cmax by 6.5% and the
ated with a shorter time to achieve higher peak mean tmax was 15% later in the treatment phase of
ibuprofen among Black volunteers and a longest concurrent administration of sucralfate in a study
time to achieve lower peak concentrations among of the single dose pharmacokinetics of ibuprofen.
144 Davies
However, no significant differences between the tered alone or with colestipol. However, cholestyr-
control and treatment phases were evident.[130] The amine co-administered with ibuprofen resulted in
influence of sucralfate co-ingestion on ibuprofen a significant decrease in the AUC (26%), Cmax
absorption demonstrated that parameters associ- (34%) and a significant increase in the tmax
ated with the rate of absorption (i.e. Cmax, tmax and (80%).[174] The bioavailability of ibuprofen when
absorption rate) were significantly altered in the administered alone or followed by colestipol hydro-
presence of sucralfate. In contrast, the relative chloride or cholestyramine demonstrated signifi-
bioavailability of ibuprofen was not significantly cant differences between treatments in terms of
different between treatments and, therefore, AUC.[333]
sucralfate does not alter the extent of ibuprofen ab-
sorption.[133] A subsequent stereospecific study 4.2 Effect of Ibuprofen on the
demonstrated that sucralfate significantly reduced Pharmacokinetics of Other Drugs
the peak concentration of S-ibuprofen and R-
It is well established that clinically important
ibuprofen when compared with fasting. However,
interactions with concomitant administration of
sucralfate did not have any significant effects on
various medications may affect the pharmacokinet-
ibuprofen pharmacokinetic parameters.[198]
ics of NSAIDs. When ibuprofen is administered
Serum concentrations of ibuprofen in 6 patients
concurrently with paracetamol there were differ-
with rheumatoid arthritis administered low dose
ences in paracetamol serum concentrations in 5 of
(10 to 20mg) methotrexate were in the usual range,
19 sampling times. However, when the bioavaila-
although immediate pre-dose trough concentra-
bility and kinetic parameters for both drugs were
tions were not consistently obtained.[332] compared there were no significant differ-
Combination analgesic products are widely used ences.[127] No consistent effect of ibuprofen admin-
on the basis that they produce a greater analgesic istration on serum salicylate concentrations have
effect and broaden the possible therapeutic uses. been demonstrated.[316]
The combination of ibuprofen and codeine may The concomitant administration of ibuprofen
have a therapeutic rationale as the mechanism of did not effect the t1⁄2β of nizatidine, however, the
analgesic action of ibuprofen is peripheral and the t1⁄2β of cimetidine was increased.[146] The pharmaco-
analgesic action may be additive with centrally kinetics of codeine either alone or in combination
acting opioids. The pharmacokinetics of ibuprofen, with ibuprofen demonstrated a lack of a pharmaco-
either alone or in combination with codeine, dem- kinetic interaction and no significant changes in
onstrated a lack of pharmacokinetic interaction and pharmacokinetic parameters.[175]
no significant changes in pharmacokinetic param- Lithium-treated patients with mania adminis-
eters.[175] tered ibuprofen demonstrated inconsistent effects
The effects of oral contraceptives and gender on on plasma lithium concentrations. However, an ad-
the pharmacokinetics of R-(–)-ibuprofen in fe- verse reaction possibly related to increased plasma
males and oral contraceptive using females versus lithium was documented in 1 patient.[334] Whether
healthy males were studied. Oral contraceptive use similar findings could be substantiated in a larger
and gender did not have any effect on inversion of population group over a more prolonged period
R-(–)-ibuprofen or on any of the other pharmaco- needs further investigation.
kinetic parameters.[210] NSAIDs are often co-administered with dis-
Patients with rheumatism may also have concur- ease-modifying antirheumatic drugs (DMARDs),
rent type II hyperlipidaemias, for which they may such as methotrexate, for the management of pa-
receive the anion exchange resins cholestipol or tients with chronic arthropathies. Six patients with
cholestyramine. There were no significant pharma- unimpaired renal function received either oral and
cokinetic differences between ibuprofen adminis- parenteral methotrexate 10 to 25 mg/dose with and
without ibuprofen 2400 mg/day for 6 weekly tion of ibuprofen (about 200 mg/L), the warfarin
doses. There was no observable interaction be- free fraction was 0.0198.[342] The effect of
tween methotrexate and ibuprofen with respect to ibuprofen on primary haemostasis in patients on
the AUC, Cmax, Cmax/dose, tmax and serum half-life warfarin therapy for venous thromboembolism
or route of methotrexate administration.[335] How- given ibuprofen 600mg 3 times daily for a week
ever, a follow-up study in patients with rheumatoid saw several patients demonstrate significant pro-
arthritis on methotrexate treated with ibuprofen 40 longation of bleeding time. In addition, plasma
mg/kg/day 3 times daily (2400 to 3600 mg/day) concentrations of ibuprofen showed a significant
demonstrated a significant reduction in the appar- correlation with bleeding time.[343]
ent systemic clearance of methotrexate as well as Many patients with hypertension may require
a reduced renal clearance and fractional excretion NSAID treatment for co-existent inflammatory
of methotrexate.[335] It would appear that variabil- disorders. However, the patients controlled with
ity among patients precludes specific recommen- hydrochlorothiazide demonstrate significant in-
dations, however, the adverse effects of such a creases in systolic blood pressure after treatment
combination should be carefully monitored. with ibuprofen and, therefore, blood pressure of
The effects of ibuprofen in daily doses of at least patients with hypertension should be carefully
1600mg of ibuprofen were studied on steady-state monitored when ibuprofen is concomitantly ad-
digoxin concentrations in patients with ischaemic ministered.[344-346] Patients with hypertension con-
heart disease. A statistically significant increase in trolled with at least 2 antihypertensive agents also
digoxin concentrations after 7 days of ibuprofen had significantly elevated blood pressure.[346] In
therapy occurred. The mean increase was 59% contrast, no significant changes with ibuprofen in
(ranging from 10.7 to 325.4%). Digoxin concen- the blood pressure of patients controlled with
trations drawn 28 days after ibuprofen initiation hydrochlorothiazide were evident.[347] In addition,
were not statistically different from baseline or 7- patients with hypertension controlled on enalapril
day digoxin concentrations.[336] A follow-up study did not demonstrate a significant change in blood
of ibuprofen 600mg 3 times daily given for 10 days pressure when ibuprofen was added to the regi-
to patients on chronic digoxin treatment demon- men.[348]
strated that ibuprofen did not change steady-state Patients with hypertension on propranolol or
digoxin concentrations. bendrofluazide given ibuprofen demonstrated a
Patients on warfarin therapy administered small but insignificant changes in blood pressure
ibuprofen for 7 days did not appear to have adverse control.[349] A case report also suggests possible
effects on anticoagulant action.[337] Patients con- delirium caused by tacrine and ibuprofen, although
trolled on anticoagulant treatment with phenpro- the mechanism of this interaction is unknown.[350]
coumon and then given ibuprofen showed no influ- A case report suggest the possibility of phenytoin
ence on the blood coagulation parameters.[338-340] toxicity induced by an interaction with ibuprofen.
Similarly, healthy male volunteers administered After taking phenytoin 300mg daily for 5 years the
warfarin 7.5mg with or without a morning dose of patient was given ibuprofen 400mg 4 times daily
ibuprofen 300 or 600mg for 14 consecutive days for degenerative rheumatic disease. The patient
did not have any alteration in the degree of developed cerebral ataxia, frontal headaches and
hypothrombinaemia or total plasma warfarin or nystagmus. The patient’s phenytoin concentrations
ibuprofen concentrations and or in coagulation pa- on admission was 101 mmol/L (therapeutic range
rameters.[341] The free fraction of warfarin in the 40 to 70 mmol/L). The mechanism of this interac-
absence of ibuprofen was 0.00978. The in vitro free tion may involve competition for hepatic micro-
fraction increased continuously with increasing somal enzymes.[351] A follow-up study of ibupro-
ibuprofen concentration. At the highest concentra- fen 1600 mg/day for 7 days on the dispositional
146 Davies
parameters of single dose phenytoin 300mg was 3. Geisslinger G, Stock KP, Bach GL, et al. Pharmacological dif-
ferences between R(–)- and S(+)-ibuprofen. Agents Actions
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cokinetics of chiral non-steroidal anti-inflammatory drugs.
7.8% but other pharmacokinetic parameters remain Eur J Clin Pharmacol 1992; 42: 237-56
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inhibition by R(–)-, S(+)- and racemic ibuprofen of human
The effect of ibuprofen on the half-life of anti- polymorphonuclear cell function in vitro. Br J Clin Pharmacol
pyrine has been studied in healthy individuals. Af- 1993; 35: 235-42
6. Evans AM, Nation RL, Sansom LN, et al. Effect of racemic
ter taking ibuprofen in a daily dose of 1200mg for ibuprofen dose on the magnitude and duration of platelet
14 days, there was no significant alteration in the cyclo-oxygenase inhibition: relationship between inhibition
of thromboxane synthesis and the plasma unbound concentra-
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Clinical Pharmacokinetics of Ibuprofen: The First 30 Years

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Clinical Pharmacokinetics of Ibuprofen: The First 30 Years

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DRUG DISPOSITION Clin Pharmacokinet 1998 Feb; 34 (2): 101-154

© Adis International Limited. All rights reserved.

Clinical Pharmacokinetics of Ibuprofen

Summary Ibuprofen is a chiral nonsteroidal anti-inflammatory drug (NSAID) of the 2

Ibuprofen is eliminated following biotransformation to glucuronide conjugate

Ibuprofen, (±)-(R,S)-2-(4-isobutylphenyl)-pro- currently used chiral NSAIDs, its anti-inflammatory

Table I. Chromatographic assays for ibuprofen

Table II. Contd

Table II. Contd

Table II. Contd

Table II. Contd

Table II. Contd

Continued over page

Table II. Contd

Table II. Contd

Table II. Contd

Table II. Contd

Table II. Contd

Continued over page

Table III. Contd

Table III. Contd

Continued over page

Table III. Contd

Table III. Contd

Table III. Contd

Table IV. Contd

Glucuronic acid conjugate Glucuronic acid conjugate

1-Hydroxy ibuprofen 2-Hydroxy ibuprofen

(+/–) Ibuprofen Glucuronic acid conjugate

3-Hydroxy ibuprofen Carboxy ibuprofen

Glucuronic acid conjugate Glucuronic acid conjugate

(–) and racemic ibuprofen was significantly longer 3. Implications of Pharmacokinetic

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