Cltn. Pharma coklnet.

28 (6): 458-470, 1995

DRUG DISPOSITION 031 2-5963/95/0006-0458/$06 SOlO

© Adis International limited All rights reserved.

Clinical Pharmacokinetics of
Lansoprazole
B. Delhotal Landes} J.P. Petite2 and B. Flouvat 1
1 Toxicology and Pharmacokinetics Laboratory; Ambroise Pare Hospital, Boulogne, France
2 Department of Hepatogastroenterology, Broussais Hospital, Paris, France

Contents
Summary . . . . . . . . . . . . . . . . . . . . . . . . 458
1. Chemical and Physical Properties of Lansoprazole 459
2. Analytical Methods " " " " " " '" 460
3. Pharmacokinetic Profile in Healthy Volunteers . . . 460
3.1 Absorption and Bioavailability .. . .. .,. . 460
3.2 Tissue Distribution and Plasma Protein Binding 462
3.3 Metabolism and Elimination . . . .. .. .. . 462
4. Influence of Age on Pharmacokinetic Profile . . 464
5. Influence of Disease on Pharmacokinetic Profile 464
5.1 Renal Failure . . 464
5.2 Hepatic Failure 465
5.3 Peptic Disease 465
6. Drug Interactions . 465
6.1 Warfarin . . . 465
6.2 Prednisone. . 466
6.3 Theophylline . 466
6.4 Phenazone (Antipyrine) 466
6.5 Diazepam 467
6.6 Antacids . . . . . . . 467
6.7 Phenytoin . .. . . . 467
6.8 Oral Contraceptives 467
7. Clinical Considerations . 467
7.1 Clinical Indications and Efficacy 467
7.2 Dose . . . . . . . . . . . . . . . . 468
7.3 Clinically Relevant Drug Interactions. 468
7.4 Tolerability . . ... . . . .. ... . . 468
7.5 Consequences of Hypochlorhydria . 469

Summary Lansoprazo\e, a benzimidazole derivative with antisecretory and antiulcer ac-

tivities, inhibits the acid pump activity at the final stage of the enzyme process
and therefore reduces the acid secretion of parietal cells. Lansoprazole is con-
verted to active metabolites in the acid environment of these cells. It is rapidly
absorbed from a gastric acid-resistant formulation and is approximately 97 %
bound in human plasma.
Single dose pharmacokinetics of lansoprazole appear to be linear over the
Lansoprazole Pharmacokinetics 459

range from 15 to 60mg. Food and time of dose influence absorption after single
doses, but do not modify the antisecretory effect of multiple doses. Lansoprazole
is extensively metabolised following oral administration into sulphone and
5-hydroxylated metabolites by the cytochrome P450 enzymes CYP3A4 and
CYP2CI8. Two other metabolites have been identified in plasma: sulphide and
hydroxylated sulphone.
Mean plasma elimination half-life (V/ 2) is between 1.3 and 2.1 hours in healthy
volunteers. 15 to 23% of the total dose is found in urine as free and conjugated
hydroxylated metabolites, while unchanged lansoprazole is not detected. The
pharmacokinetic profile of the drug is not modified by multiple administration.
In healthy elderly volunteers, area under the plasma concentration-time curve
(AVC) and t'/2 are significantly greater after single administration than that in
young volunteers; accumulation from repeated daily administration occurs to the
same extent as in young volunteers.
Renal failure has no influence on the pharmacokinetics of lansoprazole, but
severe hepatic failure causes a significant decrease in clearance and an increase
in the AVC and tl/2 of lansoprazole. This is accompanied by modifications in the
AVC of metabolites, but severe hepatic failure has minimal effect on accumula-
tion of the drug after multiple administration. The pharmacokinetics of lansopra-
zole in patients with acid-related disorders do not differ from those in healthy
volunteers. Studies of interactions of lansoprazole with warfarin, prednisone,
theophylline, phenazone (antipyrine), diazepam, phenytoin and oral contracep-
tives suggest minimal risk of any clinically significant interaction.

Lansoprazole, structurally related to omeprazole,
is a substituted benzimidazole and is a specific in-
hibitor of H+/K+ -ATPase or the ' proton pump'.
This enzyme catalyses the final step in the acid se-
cretion pathway in gastric parietal cells. Lansopra-
zole is a prodrug that is converted to active meta-
bolites in the acid environment of parietal cells.
Oral administration of lansoprazole to humans re-
sults in a dose-dependent inhibition of acid se-
cretion in the dose range of 15 to 60mg. Inhibition
is approximately 80% after an initial dose of 30mg,
and 90% after 7 days' treatment with lansoprazole
30 mg/day.
At dosages of 30 mg/day, lansoprazole is effec-
tive in the treatment of various peptic diseases,
including gastric and duodenal ulcer and reflux
oesophagi tis refractory to histamine H2-receptor
antagonists. At higher dosages lansoprazole is ef-
fective in the treatment of Zollinger-Ellison syn-
drome.[l]
The clinical pharmacokinetics of lansoprazole
and the clinical implications of its pharmacokinetic
profile are reviewed here.
1. Chemical and Physical
Properties of Lansoprazole
The molecular structure of lansoprazole con-
sists of a substituted pyridine ring with a trifluoro-
ethoxy group linked to a benzimidazole by a
methyl sulphoxide (fig. 1).
The molecular weight of lansoprazole is 369D.
Lansoprazole is a weak base (pKa = 8.5), freely
soluble in dimethylformamide and methanol,
partially soluble in alcohol (ethanol), virtually in-
soluble in water at pH 11 and unstable in an acid
environment. A capsule containing enteric-coated
granules has, thus, been formulated to prevent gas-
tric decomposition.
Lansoprazole has a chiral centre at its asymmet-
ric sulphinyl group, but has been commercially
marketed as a racemic mixture. Both the (+)- and
(-)-enantiomers of lansoprazole inhibit acid for-
mation stimulated by dibutyril cyclic adenosine

© Adis International Limited. All rights reserved. Clin. Pharmacokinet. 28 (6) 1995
460
Lansoprazole
Formula
Lansoprazole
Sulphone metabolite
5-Hydroxy-lansoprazole
Sulphide metabolite
Hydroxy-sulphone metabolite
Hydroxy-sulphide metabolite
Fig_1. Structures of lansoprazole and its metabolites.
monophosphate (AMP) in canine isolated parietal
cellsJ2]
2. Analytical Methods
High performance reverse phase liquid chro-
matography in isocratic conditions is commonly
used for the separation of lansoprazole and its me-
tabolites, with ultraviolet detection at 285 and
303nm.[3,4]
The drug is unstable in slightly acid solutions,
but is highly stable in organic solutions (methanol,
dimethylformamide) at room temperature. Precau-
tions are required during the extraction and injec-
tion processes.
Extraction of lansoprazole and its metabolites
from biological fluids into an organic phase (di-
ethyl ether/dichloromethane,[3] tert-butyl methyl
ether[4]) has been performed at the pH of biological
fluids, with an extraction coefficient of more than
75%. Solid phase extraction is unworkable.[4]
Liquid chromatography injection uses an auto-
sampler with cooling device[3] or automatic injec-
tion via a loop columnJ4] Quantification limits are
5[3] and 2 IlglL[4] for plasma volumes of 0.5 and
Iml, respectively.
Methods are also available for the determination
of lansoprazole and its metabolites in urine. Urine
© Adls International limited. All rights reserved.
Delhotal Landes et a/.
is incubated with ~-glucuronidase at pH 7 to deter-
mine glucuronide metabolites in urine.
3. Pharmacokinetic Profile in
Healthy Volunteers
3.1 Absorption and Bioavailability
R1 R2 No study has yet been published investigating
0 H
intravenous and oral administration of lansopra-
02 H zole in a crossover study design. Therefore, precise
0 OH
H information concerning the absolute bioavailabil-
~ OH ity of the gastric acid-resistant capsules used in
OH
clinical and pharmacokinetic studies is not avail-
able. However, on the basis of preliminary results
from an as yet unpublished study (data on file, Ab-
bott Laboratories), Hussein et aLl5] reported that oral
capsules had bioavailability of more than 85%.
3. ,_ , Single Dose
Following administration of lansoprazole 15 to
60mg after a fast, the time taken to achieve maxi-
mal plasma concentrations (t max ) was not dose-
dependent, with mean tmax values of between 1.1 and
2.2 hours. Maximal plasma concentrations (C max )
showed an approximate linear increase in relation
to the dose administered, as did the area under the
plasma concentration-time curve [AUC(O-24h)] [5-7]
(table I).
Following morning administration of 30mg of
lansoprazole as enteric-coated granules after an
overnight fast, lansoprazole was found in blood 30
minutes postdose. C max was between 750 ± 331
and 1173 ± 333 Ilg/L (table 1)[5-7], and there was
wide interindividual variability.
A study involving 12 healthy volunteers, in
which lansoprazole 30mg was administered either
in the morning after a fast or in the evening, dem-
onstrated that the rate of absorption following eve-
ning administration was slower (tmax 2.8 ± 1.3 vs
1.3 ± 0.5 hours) and bioavailability was lower:
C max and AUC(O-24h) were decreased by hal0 7]
A study involving single oral administration of
lansoprazole 30mg to 9 women and 9 men, evalu-
ated the influence of gender on the pharmacokinet-
ics of lansoprazole (table II). The various parame-
ters showed no significant difference between the
Clin. Pharmacokinet. 28 (6) 1995
Lansoprazole Pharmacokinetics 461

Table I. Mean (± SD) pharmacokinetic parameters of lansoprazole in various patient groups

Dose (mg) No. of individuals tmax C max AUC(o.24h) t1",~ Reference
or dose/24h (mg) (h) (mg/L) (mg/L. h) (h)

Administration in the morning to fasting young individuals

15 12 1.2±0,4 0,41 ± 0.2 0.95±0.59 1.3 ± 0.5 5
30 12 1.5±1 0.75±0.33 1.76 ± 1.06 1.3±0,4 5
15 6 2.1 ±0.7 0.53±0.27 2.18±2.19 1,4±1 .1 6
30 6 2±0.5 1.04±0.33 3.89 ± 2,48 1,4 ± 1 6
60 6 2±0,4 2.17±0.73 9,48 ± 5.23 1.7±0.7 6
30 12 1.3±0.6 0.88± .55 2.2 ± 1.76 2.1 ±2.5 7
30 12 1.5 ± 0.5 1.15±0.34 2.98 ± 1.78a 1.6± 1.2 8

Factors influencing the pharmacokinetic profile of lansoprazole

Age
Young volunteers
12 15 (day 7) 1.3 ± 0.7 0,4 ± 0.21 1.01 ±0.86 1,4±0.6 5
12 30 (day 7) 1.5 ± 0.7 0.74 ± 0,41 2.07 ± 1,47 1,4±0.6 5
Elderly volunteers
12 15 (day 1) 1.5±0.5 0,45 ± 0.15 1.33±0.67 1.9±0.9 5
12 30 (day 1) 1.6±0.9 0.77 ± 0.25 2.68±1.14 1.9 ± 0.8 5
12 15 (day 7) 1,4 ± 0.3 0,43 ± 0.13 1,48 ±0.72 2.2± 1.2 5
12 30 (day 7) 1.1 ±0.5 0.95±0.31 2.86 ± 1.09 2.1 ±0.9 5
12 30 (day 1) 1.5 1.15 ± 0.54 5.22 ±3.86a 2.9 ± 1.2 9
12 30 (day 7) 1.5 1.28 ±0.54 5.70±4.13 2.7 ± 1.2 9
Timing of administration
Administration with food
6 30 3.3 ± 0.78 0.68 ±0.36 3.32±2.65 1.6 ±0.9 6
12 30 3.7± 1.2 0.6 ±0.33 2.24 ± 1.63a 1.5 ± 0.6 8
Administration in the morning
12 30 (day 7) 1.3±0.5 1.05±0.38 2.52 ± 1.74 2,4 ± 1.9 7
Administration in the evening
12 30 (day 1) 2.8 ± 1.3 0.37±0.23 0.99 ± 0,47 2.4 ± 1.8 7
12 30 (day 7) 2.1 ± 0.8 0.38±0.25 1.06 ±0.68 1.4 ± 0.3 7
a Area under the plasma concentration-time curve from zero to infinity measured.
Abbreviations: AUC(o.24h) = area under the plasma concentration-time curve from zero to 24 hours; Cmax = maximum plasma drug
concentration; tmax = time to Cmax; t1",~ = terminal elimination half-life.

2 groups, with only interindividual variability ap-
pearing to be greater in men than women.
The influence of food has been evaluated in 2
studies: one consisted of 6 healthy male volun-
teers[6] and the other of 12 healthy volunteers, of
whom 6 were male and 6 were female)8] Lansopra-
zole was administered either after an overnight
fast, after breakfast or during a test meal.
When iansoprazole is administered with a meal,
the bioavailability of the drug is reduced, both in
terms of Cmax (l.5- to 2-fold decrease) and the
amount absorbed [AUC co- 24h)]. Relative bioavaila-
bility in this situation compared with that measured
when lansoprazole is given after a fast was 0.85[6]
and 0.77,[8] respectively. Absorption was delayed,
with a l.5- to 2-fold increase in tmax and a lag time
greater than 30 minutes when the drug was given
with food. The apparent plasma tl/2of lansoprazole
was unaffected by the presence of food.
3. 1.2 Multiple Dose Studies
Doses of 15 or 30 mg have been given daily for
7 days with pharmacokinetic evaluation occurring
on days 1 and 7)5-7,10] The rate of absorption
showed no change after 7 days of repeated admin-

© Adis International Limited. All rights reserved. Clln. Pharmacoklnet. 28 (6) 1995
462 De/hotal Landes et al.

Table II. Pharmacokinetic parameters of lansoprazole (mean ± SO) after the administration of 7 daily doses of 30mg
in young individuals (9 male and 9 female) after administration of a
single oral dose (30mg) to fasting individualsl71
of lansoprazole either before or after food.
Parameter Male Female p
3.2 Tissue Distribution and
tmax (h) 1.4 ± 0.4 1.6±0.5 NS
Cmax (mg/L) 0.92±0.5 1.15±0.28 NS
Plasma Protein Binding
AUC(o_ J (mg/L· h) 2.40 ± 2.11 2.93± 1.33 NS
Plasma protein binding of lansoprazole in
tl;'~ (h) 1.6±1 .0 1.3±0.5 NS
CUF(Uh/kg) 0.28±0.17 0.24±0.10 NS
healthy individuals is 97%,[7] The in vitro binding
Vd/F (Ukg) 0.46 ± 0.24 0.41 ±0.08 NS of lansoprazole to proteins was 98 % within a range
MR hydroxy- 0.065 ± 0.059 0.059 ± 0.056 NS of lansoprazole concentrations of 0.01 to 5 mg/L
LAN/LAN (S. Urien, personal communication). Binding was
MR sulphone/LAN 0.111 ±0.176 0.042 ± 0.022 NS 96% to albumin and 2% to acid (Xl-glycoprotein.
MR sulphide/LAN 0.017 ± 0.041 0.020 ± 0.023 NS
There was no evidence of binding to red blood cells.
Abbreviations: AUC(o_) = area under the plasma concentration-time
curve from zero to infinity; AUCLAN = AUC(o_) for lansoprazole;
No data are available concerning the distribu-
AUCmel = AUC(o- ) for the metabolite; CUF = oral body clearance tion of lansoprazole in human tissues after intrave-
of drug from plasma; C max = maximum drug concentration ; nous administration of the drug. Nevertheless,
LAN = lansoprazole; sulphide = sulphide metabolite of lansopra-
=
zole; sui phone sui phone metabolite of lansoprazole; tmax time = Chassard et alJ 13 ] reported a decrease in volume of
to Cm,x; tl;'~ = terminal elimination half-life; MR = metabolite ratio distribution when the dose administered by a 10
[(AUCmet/AUCLAN) x (369/MWmet)] ; MWmet = molecular weight of minute infusion to healthy volunteers increased
the metabolite; NS = no statistically significant difference between
groups, p > 0.05 (ANOVA); Vd/F = oral apparent volume of dis-
from 15 to 90mg. The apparent oral volume of dis-
tribution. tribution (V d/F) is approximately 0.5 Llkg follow-
ing oral administration of 30mg (see table II).

istration, with tmax values being similar to those
that occurred after the first dose (table I). A linear
correlation between Cmax and AUC(O-24h) with the
administered dose was identical to that of a single
dose, with the same wide interindividual variabil-
ity. Neither Cmax or AUC(O-24h) provided any evi-
dence of accumulation at the doses used.
During multiple administration, the influence of
the time of administration (in the evening or in the
morning after an overnight fast) was identical to
that reported following administration of a single
dose.[7] Nevertheless, Hongo et alJll] found no dif-
ference between the antisecretory effect of lan-
soprazole, evaluated by intragastric pH monitoring
in 8 healthy male volunteers following the admin-
istration oflansoprazole 30 mg/day, either morning
or evening, for 7 days.
The effects of a meal on the pharmacokinetic
profile of lansoprazole during multiple administra-
tion have not been studied. However, Moules et al.[l2]
showed that the gastric inhibitory effect of lan-
soprazole was unaffected by the presence of food
3.3 Metabolism and Elimination
The elimination of lansoprazole is almost en-
tirely by metabolism, which is presumed to occur
mainly in the liver. Metabolites are themselves pro-
drugs, which are converted in the acid environment
of parietal cells into active metabolites, chiefly a
cyclic sulphenamide and a disulphide. These ac-
tive metabolites react with the sulphydryl groups
of ATPase. [14] These metabolites are not found in
blood.
Lansoprazole is the major compound in plasma,
being accompanied by 2 chief metabolites, i.e. the
benzimidazole ring 5-hydroxylated metabolite and
the sulphone, which is formed by oxidation of the
sulphoxide radical[6-8,15] (fig. 2). The sulphide, re-
sulting from the reduction of lansoprazole, is also
present in smaller amounts.[8] The tmax values for
these 3 metabolites were similar to that for the par-
ent drug. In an unpublished study we found the
hydroxylated metabolite of the sulphone in the
blood of young volunteers following oral adminis-
tration of 60mg. Two hours after the administration
of 30mg of lansoprazole, the concentration of sul-

© Adis International Limited. All rights reserved. Clin. Pharmacokinet. 28 (6) 1995
Lansoprazole Pharmacokinetics
Sulphide
metabolite
H
J8C
Hydroxy-sulphide
metabolite
Glucuroconjugated: Yes
Fig. 2. Metabolic pathways of lansoprazole, for structures of metabolites see figure 1. Symbol: ? indicates that metabolism possibly
occurs via this pathway.
phone was 0.0078 ± 0.0024 mg/L and that of
hydroxy-Iansoprazole was 0.0074 ± 0.0054 mg/L
when the plasma concentration of lansoprazole
was 0.997 ± 0.33 mg/L. According to Delhotal
Landes et al. ,[8,15] the sulphone metabolite had a
C max equal to 8% of that of lansoprazole and an
AUC equal to 14% of that of the parent drug. The
5-hydroxylated metabolite had a Cmax and AUC of
6 and 4%, respectively, of those of lansoprazole.
The sulphide accounted for 1.5% of circulating
lansoprazole (see table III).
According to Hussein et al.,[5] plasma metabo-
lite concentrations were below their limits of de-
tection after administration of 15 or 30mg to young
or elderly individuals. No difference in metabolic
ratios for the 3 distinct metabolic pathways in men
and women suggest that the metabolism of lan-
soprazole is similar in both genders (table 11).
The administration of food with lansoprazole
has no effect on the metabolic ratio of sui phone,
hydroxylated and sulphide metabolites.[8]
Urinary elimination of lansoprazole is essentially
in the form of glucuroconjugated metabolites of
its hydroxylated derivatives (hydroxy-Iansoprazole,
© Adls International limited. All rights reserved.
463
Sulphone
metabolite
\HoCY~7
~y~-CH2:yN
~ I ~ I N
H3C
OCH2CF3
Lansoprazole
CYP3A4 CYP2Cj
? ? Hydroxy-sulphone
- 5-Hydroxy-lansoprazole - metabolite
Yes Yes
Urine and biliary elimination
hydroxysulphone and the hydroxysulphide deriva-
tive; fig. 2) and elimination in the unconjugated
form is negligible -less than 2% of the dose. Fol-
lowing repeated administration for 7 days, 15% of
the total dose was excreted in urine as metabolites,
with no detection of unchanged lansoprazole.[6]
Following a single 30mg dose, 23% of the dose
was found in the urine of young volunteers in the
form of free and conjugated metabolites.[15]
Data from studies using human liver micro-
somes and isolated hepatocytes indicate that the
cytochrome P450 enzyme CYP3A4 is the major
enzyme involved in sulphone formation, while the
production of hydroxy-Iansoprazole could be par-
tially mediated by CYP3A4 and CYP2C18 (and/or
another CYP2C-related form).[l6] In contrast to
omeprazole, CYP2C 19 (CYP2Cmephenytoin) is not
implicated in the formation of hydroxylated meta-
bolites of lansoprazole.
Studies involving young volunteers (table I)
have shown that lansoprazole has a short tY2 of 1.2
to 2.1 hours following the administration of 30mg
enteric-coated capsules. The elimination tY2 of
lansoprazole did not change significantly after re-
Clin. Pharmacokinet. 28 (6) 1995
464 Delhotal Landes et al.

Table III. Pharmacokinetics of lansoprazole metabolites following administration of a single dose of 30mg in the morning (mean ± 8D)[8.9· 15J
Young Elderly CRF Hepatitis CC UCC

Sulphone metabolite
tmax (h) 1.6±0.6 1.S±O.4 1.B ± 0.B 4.4 ± 2.S S.B ± 3.2
Cmax (mg/L) 0.09 ±0.09S 0.06 ± 0.04 0.11±0.7 0.2S ± 0.12 0.34±0.14
MR 0.OB±0.147 0.09 ± 0.11 0.04 ± 0.03 0.13±0.OB 0.32 ± 0.19 0.SB±0.3
AUC (mglL· h) 0.46 ± 0.B4

5-Hydroxy-lansoprazole
tmax (h) loS ± O.S 1.2 ± 0.3 1.3 ± 0.6 1.9 ± O.S 1.7±0.9
Cmax (mg/L) 0.07 ±O.OS 0.OS±0.03 0.03 ± 0.02 0.02±0.02 0.01 ±O.OOB
MR 0.06 ±0.06 0.07 ± 0.04 O.OS ± 0.04 0.04 ± 0.04 O.OOB ± 0.009 0.006 ± O.OOS
AUC (mglL· h) 0.11 ±O.OB

Sulphide metabolite
tmax (h) 1.7 ± 1.0 1.7± 1.0 2.3±0.9 3.4 ± 1.2 3.B ± 2.4
Cmax (mg/L) 0.02±0.02 0.D1 ± 0.D1 0.03 ±0.04 0.03±0.01 0.02±0.01
MR 0.02 ± 0.03 O.OOB ± 0.006 0.009 ±0.01 0.04 ±O.OS 0.03 ± 0.D1 0.03 ± 0.02
AUC (mg/L· h) 0.04±0.06
Abbreviations: AUC =area under the plasma concentration-time curve from zero to infinity; AUCLAN =AUC of lansoprazole; AUCmet =AUC of the
metabolite; CC = patients with compensated cirrhosis; Cmax = maximum drug concentration; CRF = patients with severe renal failure;
MR = metabolite ratio [(AUCmet/AUCLAN) x (369/MWmet)]; MWmet = molecular weight of the metabolite; tmax =time to Cmax; UCC = patients
with uncompensated cirrhosis.

peated administration, nor did it change in relation
to dose increase, gender or the time of administra-
tion. It should nevertheless be noted that in an un-
published study we found that among young vol-
unteers administered orallansoprazole 30mg, 2 of
18 individuals had a tyz value longer than 4 hours,
and the metabolic ratio (sulphone to lansoprazole)
was greater than 0.4.
The total clearance of lansoprazole after single
intravenous administration decreases with the dose
administered: 17 Lih after 15mg, 15 Lih after 30mg,
13 Lih after 60mg and 11 Llh after 90mg. In con-
trast, the terminal tY2 remained unchanged and was
approximately 1 hour)l3]
4. Influence of Age on
Pharmacokinetic Profile
No data are available concerning the pharmaco-
kinetic profile of lansoprazole in children and in-
fants.
Administration of a single oral dose oflansopra-
zole 30mg resulted in a 50% increase in AVC and
a 40% increase in tyz in 12 healthy elderly volunteers
(mean age of 65 years), with normal renal function,
as compared with a control group of 12 younger
(mean age 38 years) volunteers.l5 ] Oral clearance de-
creases with age. AVC and tyz were significantly
greater (90 and 100%, respectively) in an elderly
group, with a mean age of 83 years, as compared with
values in younger volunteers (mean age 24 years).l9]
However, Cmax and tmax did not differ between the
younger and older groups. Pharmacokinetics in the
elderly are linear after single and repeated doses of
15 and 30 mg/day for 7 consecutive days and the
drug does not accumulate (see table I).
Plasma concentrations of detectable metabolites
in younger volunteers were similar to those found
in the elderly; the metabolic ratio was similar in
both patient groups)9] The hydroxylated metabo-
lite of the sulphone was detected in elderly volun-
teers, but not in younger individuals, after a dose
of30mg.
5. Influence of Disease on
Pharmacokinetic Profile
5.1 Renal Failure
After administration of a single 30mg dose, the
pharmacokinetics of lansoprazole in patients with

© Adis International Limited. All rights reserved. e lin. Pharmacokinet. 28 (6) 1995
Lansoprazole Pharmacokinetics 465

chronic renal failure and a creatinine clearance be-
tween 20 and 40 rnl/min (1.2 and 2.4 Lib) [6 pa-
tients], or below 20 mllmin (1.2 Llh) [5 patients]
did not differ significantly from values found pre-
viously in healthy individuals (table IV).[15] The
plasma tl/2 of lansoprazole did not change in rela-
tion to the degree of renal impairment, nor was
clearance or volume of distribution affected by re-
nal function. Only urinary extraction of lansoprazole
was markedly decreased in relation to creatinine
clearance.
5.2 Hepatic Failure
The oral pharmacokinetic profile of lansopra-
zole was studied in 8 patients with acute hepatitis
and in 16 patients with cirrhosis, decompensated
cirrhosis in half of the patients.[15] Following a sin-
gle dose, absorption was delayed, with a signifi-
cantly longer tmax in these patients than in healthy
volunteers. However, there was no change in Cmax .
AUC increased with the degree of hepatocellular
impairment, with a significant increase in plasma
elimination. There was a correlation between the
clearance of lansoprazole and that of bromo-
sulphophthalein (BSP). The metabolic ratio of the
sulphone was significantly increased and that of
the hydroxylated metabolite decreased in compar-
ison with healthy volunteers (tables III and IV).
Identical results were obtained in another study
when lansoprazole 30 mg/day was given to 12 pa-
tients with cirrhosis for 9 days: 3 graded A, 1
graded Band 8 graded C by the Child Pugh classi-
fication.[17] The tY2 of lansoprazole remained un-
changed between the first and last dose (6.4 ± 1.4
vs 6.3 ± 1.7 hours) and the accumulation ratio cal-
culated from the AUC was 1.67 ± 0.43. Diffusion
in ascitic fluid represented only lO% of the plasma
concentrations of drug.
5.3 Peptic Disease
In an unpublished study, we measured the effi-
cacy of lansoprazole by repeated administration of
the drug to lO patients (mean age of 48 ± 20 years)
with either a gastric ulcer, duodenal ulcer, oeso-
phagitis, chronic gastritis or chronic duodenitis,
but free of any other disease. The study showed
that the pharmacokinetics of lansoprazole were un-
modified in these patients. On the seventh day of
administration of lansoprazole 30 mg/day, tY2 was
2.4 ± 1.8 hours, AUC(o.24h) 2.9 ± 2.5 mg/L • hand
C max 0.67 ± 0.37 mg/L.
6. Drug Interactions
Lansoprazole, by binding to hepatic cytochromes
P450 and blocking gastric acid secretion, may
modify the oxidative metabolism or absorption of
certain drugs . This section reviews drug-drug in-
teractions reported in the literature.
6.1 Warfarin
A group of 24 healthy volunteers took warfarin
for 9 days at doses adjusted to produce a prothrom-
bin time of 16 to 18 seconds.l 18 •19] They also took
lansoprazole 60mg or placebo daily for 7 days.

Table IV. Pharmacokinetics of lar.soprazole following administration of a single dose of 30mg in the morning (mean ± SD)1151
Young CRF Hepatitis CC UCC
tm,x (h) 1.5 ± 0.5 1.4 ± 0.2 1.4 ± 0.6 2.1 ± 0.5 2.1 ± 0.6
Cmax (mg/L) 1.03 ± 0.4 0.94 ± 0.28 1.08 ± 0.66 1.44 ± 0.28 1.14 ± 0.38
AUC (mg/L • h) 2.67 ± 1.73 2.78± 1.67 5.2 ± 5.44 11.7 ±3.24 10.7±6.03
\1,j,~ (h) 1.4 ± 0.8 1.62±0.71 3.2 ±2.07 6.1 ± 1.51 7.2±2.5
CUF (Uh/kg) 0.26±0.14 0.21 ± 0.11 0.19 ± 0.14 0.04± 0.02 0.07 ± 0.06
Vd/F (Ukg) 0.45 ± 0.18 0.41 ±0.11 0.57 ±0.25 0.35±0.06 0.55 ± 0.23
fe(%) 23 4.3 27 21 23
Abbreviations: AUC = area under the plasma concentration-time curve from zero to infinity; CC = patients with compensated cirrhosis;
= = =
CUF apparent oral body clearance of drug from plasma; Cm,x maximum plasma drug concentration ; fe % of dose eliminated in
= = =
the urine as free and conjugated metabolites; CRF patients with renal failure; tm,x time to Cm,x; tlf.!~ terminal elimination half-life;
UCC = patients with uncompensated cirrhosis; Vd/F = oral apparent volume of distribution.

© Adis International Limited. All rights reserved. Clln. Pharmacokinet. 28 (6) 1995
466
Coadministration of lansoprazole did not affect ei-
ther steady-state pharmacokinetic parameters [t max ,
Cmax, minimal plasma concentrations (Cmin), AVq
of the S- and R-enantiomers of warfarin or mean
prothrombin time during the final 3 days of drug
administration. This study indicates that lansopra-
zole can be given with warfarin without any need
to adjust the dose of warfarin and with only a min-
imal risk of any clinically significant interaction.
6.2 Prednisone
Adverse effects have been reported when om-
eprazole was added to prednisone in patients with
skin disease. Therefore, a crossover study was un-
dertaken in 18 healthy individuals to evaluate po-
tential drug interactions between a substituted
benzimidazole and prednisone PO] The pharmaco-
kinetics of a single dose of 40mg of prednisone
were studied before and after administration of
lansoprazole 30mg (or omeprazole 40mg) daily
for 7 days. The investigators did not note any mod-
ification of the absorption of prednisone, of
bioconversion of prednisone to prednisolone, or
disposition of prednisolone with any of the treat-
ment regimensVO]
6.3 Theophylline
The pharmacokinetics of orally administered
theophylline 200mg administered 4 times daily for
10 consecutive days were evaluated in 14 volun-
teers after administration of a single dose of 60mg
of lansoprazole or placebo (day 4) and at steady-
state after 7 doses of lansoprazole or placebo (day
1O).l21] Only a slight decrease in the AVC of theo-
phylline was seen following administration of a
single dose of lansoprazole. Following 7 days of
treatment with lansoprazole, significant, but slight,
decreases in Cmin and AVC were noted. This sug-
gests that lansoprazole may be given with theo-
phylline with minimal risk of any significant inter-
action.
In a separate study,[22] 2 groups of 8 healthy in-
dividuals were given 300mg of theophylline by in-
travenous infusion before treatment and on the
fourteenth day of daily administration of either 30
© Adis International Limited . All rights reserved.
Delhotal Landes et al.
or 60mg of lansoprazole. The t Y2 of theophylline
following the administration of lansoprazole was
slightly decreased, without any change in volume
of distribution at steady-state (V ss ). Total body
clearance and metabolic clearance were increased
nonsignificantly by 11.2 ± 18% and 15 ± 32%,
respectively, with 30 mg/day and by 10.3 ± 6.3
(p < 0.01) and 8.7 ± 22.6% (nonsignificantly), re-
spectively, with 60 mg/day. Significant induction
of dealkylation and hydroxylation of theophylline
to 3-methylxanthine and 1-methyluric acid were
found only in the group of patients receiving
lansoprazo1e 30mg. The effects of lansoprazole, in
terms of a slightly higher clearance of theophylline
and considerable interindividual variability, sug-
gest the need for drug monitoring of theophylline
when lansoprazole is administered concomitantly.
6.4 Phenazone (Antipyrine)
Roux et al.,[22] using the same protocol de-
scribed for theophylline (section 6.3), found that
only the 60mg dose of lansoprazole induced deal-
kylation and hydroxylation of 19 of phenazone
(antipyrine) administered by infusion. The meta-
bolic clearance of 3-hydroxymethyl-phenazone,
norphenazone and 4-hydroxy-phenazone were sig-
nificantly increased by 19, 36 and 26%, respec-
tively (p < 0.01). The t Y2 of phenazone was signif-
icantly decreased (9.7 vs 1l.1 hours, P < 0.05).
The effects of single and multiple doses of 60mg
of lansoprazole on the pharmacokinetics of infused
phenazone and indocyanine green have been eval-
uated in 16 healthy male volunteers.[23] A single
dose of lansoprazole had no significant effect on
the pharmacokinetics of the 2 substances. After the
seventh dose, the clearance of indocyanine de-
creased by 11 % and that of phenazone increased by
5%. The investigators suggested that clinically sig-
nificant interactions between lansoprazole and
other drugs would not be expected on the basis of
altered intrinsic metabolic clearance or hepatic
blood flowV3]
Clin. Pharmacokinet. 28 (6) 1995
Lansoprazole Pharmacokinetics
6.5 Diazepam
The influence of 10 days of treatment with
lansoprazole 60mg on the pharmacokinetics of sin-
gle-dose intravenous diazepam 0.1 mg/kg was in-
vestigated in 12 healthy male volunteers.[24] No
significant changes in the pharmacokinetic param-
eters of diazepam or in mean plasma concentra-
tions of demethyldiazepam were seen were the
drug was given with lansoprazole. Long term treat-
ment with a therapeutic dose of lansoprazole does
not interfere with diazepam metabolism.
6.6 Antacids
Concomitant administration of antacids (alu-
minium and magnesium hydroxides) to 12 healthy
individuals[81 decreased the rate of absorption of
enteric-coated granules of lansoprazole 30mg.
AUC decreased slightly, but not significantly,
(2.6 ± l.97 vs 2.98 ± l.78 mglL. h) and Cmax de-
creased significantly (842 ± 447 vs 1151 ± 344
j.1g/L, P < 0.05). Similarly, Gerloff et alPS] re-
ported a significantly lower Cmax for lansoprazole
during coadministration of magaldrate [446 ± 181
(monotherapy) vs 621 ± 241 j.1g/L (combination
therapy)). In 2 studies the tmax and tY2 of lan-
soprazole were unchanged after coadministration
with antacids. Coadministration of antacids does
not appear to influence the absorption of lansopra-
zole to any clinically relevant extent. Administra-
tion of lansoprazole 1 hour after administration of
an antacid did not modify any of the pharmacoki-
netic parameters of lansoprazole.[8]
6.7 Phenytoin
In 12 healthy adult male volunteers, 60mg of
lansoprazole once daily for 7 days increased the
AUC of intravenously administered phenytoin
250mg by less than 3% compared with placebo
(132 ± 37.5 vs 128 ± 36.6 mg/L. h).[26] This differ-
ence is of no clinical significance.
6.8 Oral Contraceptives
In a placebo comparison in 24 healthy women
who were extensive metabolisers of sparteine and
© Ad is International Limited. All rights reserved.
467
mephenytoin, lansoprazole 60mg once daily from
day 1 to day 21 of a menstrual cycle did not alter
plasma concentrations of ethinylestradiol and
levonorgestrel administered as a monophasic low-
dose oral contraceptive containing 0.03mg ethinyl-
estradiol and 0.15 mg levonorgestreU 27 ]
7. Clinical Considerations
7.1 Clinical Indications and Efficacy
Together with omeprazole and pantoprazole,
lansoprazole forms the group of 'proton pump in-
hibitors' (PP!). These agents are extremely effec-
tive gastric anti secretory agents.
Given to healthy volunteers at the dosage of 30
mg/day, lansoprazole decreases basal acid output
by 71 % and stimulated acid output by 81 % from
the first day onwards. After 7 days' administration,
basal acid output is decreased by more than 80%,
stimulated acid output by 85 to 90% and the per-
centage time at gastric pH> 3 is 58% during the
24-hour period. These effects are rapidly reversible
when the drug is stopped, without any rebound
phenomenon (J.P. Petite, personal communica-
tion). Lansoprazole is thus indicated in all disor-
ders in which gastric acid secretion is involved.
During the treatment of acute exacerbations of
duodenal ulcer, healing rates obtained with
lansoprazole are far greater than those associated
with histamine H 2-receptor antagonists. After 2
weeks of treatment, 74 to 78% of duodenal ulcers
were healed with lansoprazole (30 mg/day) and
only 46 to 60% were healed with ranitidine (300
mg/day). After 4 weeks of treatment, virtually all
duodenal ulcers (93 to 95%) are healed with
lansoprazole (30 mg/day), while ranitidine (300
mg/day) healed 79 to 89% of patients according to
different studies.[28-30]
In 2 trials, lansoprazole (30 mg/day) healed du-
odenal ulcers faster than omeprazole (20 mg/day):
after 2 weeks, 74 and 80% of ulcers were healed
following treatment with lansoprazole vs 58 and
64% with omeprazolePl ,32] After 4 weeks of treat-
ment efficacy were the same for the 2 PPIs.
Clin. Pharmacokinet. 28 (6) 1995
468
Lansoprazole (30 mg/day) is also clinically use-
ful for the treatment of gastric ulcers: 80 to 88% of
ulcers were healed in 4 weeks and 98 to 100% were
healed after 8 weeks of treatment.l 33 ,34] These fig-
ures are markedly better than those obtained with
ranitidine (300 mg/day) [62% at 4 weeks, 86% at
8 weeks[33]] and equivalent to those obtained with
omeprazole (20 mg/day).l34]
Lansoprazole is particularly effective for the
treatment of peptic oesophagi tis due to reflux. We
obtained a healing rate in erosive oesophagitis of
85% at 4 weeks and 95% at 8 weeks with lansopra-
zole (30 mg/day); corresponding healing rates with
ranitidine (300 mg/day) were 38 and 53%.[35]
Many studies have confirmed the marked supe-
riority of the efficacy of lansoprazole compared
with histamine H2-receptor antagonists.
Zollinger-Ellison syndrome is a less common
indication for PPIs. Two trials have shown that 60
to 90 mg/day of lansoprazole, generally given as a
single daily dose, was sufficient to eliminate symp-
tomatology and reduce basal acid output to a min-
imum.[36,37]
7.2 Dose
Several clinical trials using different doses in
patients with gastric and duodenal ulcer or oeso-
phagitis have shown that the optimal dose of
lansoprazole is 30 mg/day. The dose of 15 mg/day
gives less favourable results and a dose of 60
mg/day does not generally provide any further clin-
ical benefit, except in the treatment of Zollinger-
Ellison syndrome.
It has been mentioned that the rate of absorption
was reduced and bioavailability decreased when
30mg of lansoprazole was given in the evening
rather than the morning, or after a meal rather than
before. Despite these findings, it would appear that
antisecretory efficacy is unchanged regardless of
administration timing when lansoprazole is given
for periods of 7 days.lll ,12] It, thus, does not seem
to be absolutely necessary to prescribe lansopra-
zole in the morning on an empty stomach in indi-
vidual situations.
© Adis International Limited. All rights reserved.
DeIhotaI Landes et al.
It has also been pointed out that the pharmaco-
kinetics of lansoprazole are minimally modified in
the elderly and in patients with renal failure. No
dosage adjustment is, therefore, required in either
patient group. Hepatic failure has more of an influ-
ence on the absorption and metabolism of
lansoprazole, but it would not seem to be of any use
to decrease the dose, the clinical tolerability being
good in these patients,[17] except, possibly, in pa-
tients with major hepatic failure, in whom a dosage
. of 30 mg/day should not be exceeded.
7.3 Clinically Relevant Drug Interactions
The metabolism of lansoprazole involves cyto-
chrome P450 enzymes, and drug interactions are
hence a possibility. In actual fact, the prescription
of lansoprazole 30mg does not appear to interfere
with the pharmacokinetic parameters of warfarin,
prednisone, phenazone or diazepam. However,
lansoprazole increases the clearance of theophyl-
line slightly, without there being any apparent need
to increase the dose of theophylline when both
agents are given to patients with asthma.[38] An ini-
tial study showed a decrease in the contraceptive
effect of low-dose hormonal agents as a result of a
lansoprazole interaction, but this finding was not
confirmed in a subsequent study.[38]
7.4 Tolerability
The clinical tolerability oflansoprazole is excel-
lent. No serious adverse events have been reported
among 8561 cases collected. Diarrhoea is the com-
monest (21 %) of the mild adverse reactions re-
ported in 5.7% of all patients. This is followed by:
nausea or vomiting (13%), headache (10%), con-
stipation (9%), dyspepsia (6%), abdominal pain
(5%), vertigo (5%), skin rash (4%) and pruritus
(3%).
With more than 53 million prescription days of
lansoprazole in France in 2 years, there have been
only 112 spontaneous notifications of adverse re-
actions, including no serious events (J.P. Petite,
personal communication). These adverse reactions
are no more common among patients aged over 65
years than among younger individualsJ38]
Clin. Pharmacakinet. 28 (6) 1995
Lansoprazole Pharmacokinetics
The tolerability of lansoprazole on the basis of
laboratory parameters is also excellent. No signif-
icant change in haematological or clinical chemis-
try parameters has been reported, regardless of
treatment duration or the age of patientsJ38] No
evidence has been found of any modification of
hormone levels under the influence of treatment
(serum insulin, aldosterone, testosterone, para-
thormone, glucagon, T3 (triiodothyronine), T4
(thyroxine), thyroid stimulating hormone, luteinis-
ing hormone, somatotrophic hormone, prolactin
levels, circadian cortisol pattern).[39,40]
7.5 Consequences of Hypochlorhydria
The only laboratory abnormality frequently
seen with lansoprazole is an increase in plasma
gastrin levels. This is a physiological reaction to
the hypochlorhydria induced by treatment. This
rise in plasma gastrin most often remains within
normal limits, but may reach levels that are 2- to
3-fold greater than normal, or even more, in 5% of
patients. However, gastrin levels do not reach the
high levels often seen in patients with pernicious
anaemia or Zollinger-Ellison syndrome.
Lansoprazole-induced hypergastrinaemia may
lead to an increase in the density of gastric en-
terochromaffin-like cells, but there have never
been any reports in humans of treatment-related
dysplasia or carcinoid tumour, even when
lansoprazole has been given in high doses or for
prolonged periods.[41]
The hypochlorhydria induced by PPIs could
also encourage colonisation of the duodenum by
bacteria of oral or faecal origin.[42] However no
clinical consequences have been identified until
now. Similarly, treatment may be accompanied by
an increase in nitrite levels in the stomach, but ni-
trosamine levels have never been reported to in-
creaseJ43] Research in this field must obviously
continue, but at present no studies suggest that
PPIs have any carcinogenic potential.
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Correspondence and reprints: Dr B. Delhotal Landes,
Toxicology and Pharmacokinetics Laboratory, Ambroise
Pare Hospital, 92100 Boulogne, France.
Clin. Pharmacokinet. 28 (6) 1995