Clin , Phormocokinet. 28 (3): 216-234.

1995
DRUG DISPOSITION 03 12-5963/95/OOO3-o2 16/ S(1I.50/0

© Adis Internotionol Umited. All rights reserved.

Clinical Pharmacokinetics of
Dipyrone and its Metabolites
Micha Levy,l Ester Zylber-Katz 1 and Bernd Rosenkranz2
1 Division of Medicine, Hadassah University Hospital, Jerusalem, Israel
2 Clinical Research, Hoechst AG, Frankfurt am Main, Germany

Contents
Summary ... . . . . . . . . . . . . . . . . . . . . . 216
1. Pharmacokinetic Properties in Healthy Volunteers . 217
1.1 Assay Methodology 217
1.2 Absorption . . . . . . . . . : . 218
1.3 Distribution. . . . . . . . . . . 220
1.4 Metabolism and Elimination . 222
1.5 Acetylation Phenotyping . . 225
2. Pharmacokinetics in Special Populations . 226
2.1 Influence of Age, Gender and Ethnic Origin 226
2.2 Pregnancy .. . 227
2.3 Liver Disease. . 227
2.4 Kidney Disease 228
3. Drug Interactions . . 229
4. Dosage and Tolerability 229
5. Clinical Implications and Conclusions . 231

Summary The pharmacokinetics of dipyrone are characterised by rapid hydrolysis to the

active moiety 4-methyl-amino-antipyrine (MAA), which has 85% bioavailability
after oral administration in tablet form, and takes a short time to achieve maximal
systemic concentrations (t max of 1.2 to 2.0 hours). Absolute bioavailability after
intramuscular and rectal administration is 87 and 54%, respectively. MAA is
further metabolised with a mean elimination half-life (t I/ 2 ) of 2.6 to 3.5 hours to
4-formyl-amino-antipyrine (FAA), which is an end-metabolite, and to 4-amino-
antipyrine (AA), which is then acetylated to 4-acetyl-amino-antipyrine (AAA)
by the polymorphic N-acetyl-transferase (t1/2 of AA is 3.8 hours in rapid acetyla-
tors and 5.5 hours in slow acetylators). Urinary excretion of these 4 metabolites
accounts for about 60% of the administered dose of dipyrone. Protein binding of
the 4 main metabolites is less than 60%. The volume of distribution of MAA is
about 1.15 Llkg of lean body mass. All 4 metabolites are excreted into breast
milk.
A single-dose study (0.75, 1.5 and 3g) and a multiple-dose study (lg 3 times
a day for 7 days) revealed nonlinear pharmacokinetics consistent with a shift of
MAA metabolism from FAA to AA. Apparent MAA clearance decreased by 22%
during multiple administration. MAA clearance was reduced by 33% in the
Pharmacokinetics of Dipyrone 217

elderly. In patients with cirrhosis of the liver, the apparent clearance of all meta-
bolites is generally reduced. In patients with renal disease, apparent clearance
of MAA remains unchanged, whereas elimination of the renally excreted me-
tabolites AAA and FAA is markedly impaired. No clinically important drug
interactions have thus far been recognised. Dipyrone does not affect the phar-
macodynamic response to alcohol (ethanol), glibenclamide (glyburide), oral anti-
coagulants or furosemide (frusemide).
The low toxicity of dipyrone and its efficacy support its use in clinical practice,
despite some complex aspects of its disposition.

Dipyrone is a water soluble pyrazolone deriva-
tive available in oral, rectal and injectable forms.
Since its introduction in 1922 it has been recog-
nised as an effective analgesic, antipyretic and anti-
spasmodic drug. Some anti-inflammatory proper-
ties have also been recognised in pharmacological
models, although whether this is of any clinical
relevance is still questionable. It is indicated for
severe pain and, particularly, for pain associated
with smooth muscle spasm or colic affecting the
gastrointestinal, biliary or urinary tracts. It is also
useful for fever that is refractory to other treat-
ment.
The drug is widely used in some countries,
while in others (i.e. the US and Sweden) it has been
banned or restricted because of the risk of adverse
reactions, notably agranulocytosis. However, it has
been estimated by the International Study of
Agranulocytosis and Aplastic Anemia that the ex-
cess risk of agranulocytosis associated with any
dipyrone exposure in one treatment week is 1.1
cases per million users. In patients receiving sali-
cylates, butazones or indomethacin for any indica-
tion during a week, the estimates were 0.06, 0.2 and
0.4 per million, respectively.[I] The same study did
not find an association between aplastic anaemia
and dipyrone use.
The study of dipyrone pharmacokinetics began
in the 1970s. Initial studies using 14C-dipyrone re-
vealed that following its oral administration it is
rapidly hydrolysed in the gastric juice and under-
goes extensive and complex biotransformationP]
More recently it has been reported that after admin-
istration of 14C-dipyrone to humans more than 20
products could be discerned, most of which were
characterised by nuclear magnetic resonance spec-
troscopy or mass spectrometry (fig. 1)[3]. After oral
or intravenous administration, more than 90% of
the administered radioactivity was recovered in the
urine and less than 10% was recovered in the fae-
cesp,4] The 4 major metabolites of dipyrone are
4-methyl-amino-antipyrine (MAA), 4-amino-anti-
pyrine (AA), 4-acetyl-amino-antipyrine (AAA)
and 4-formyl-amino-antipyrine (FAA) [fig. 1],
which account for about 60% of the administered
dose.[5,6] In total 85% of all urinary metabolites
have been identified.
The analgesic effect of dipyrone was found to
be correlated with the time course of salivary MAA
plus AA concentrations. [7] The introduction of high
performance liquid chromatography (HPLC) tech-
niques allowing simultaneous determination of the
4 major dipyrone metabolites has enabled the study
of many aspects of their pharmacokinetics. The
data gathered thus far are presented in this first
review of dipyrone pharmacokinetics.
1. Pharmacokinetic Properties
in Healthy Volunteers
1.1 Assay Methodology
The 4 main metabolites of dipyrone, MAA,
AA, AAA and FAA, have been determined in hu-
man plasma (or serum), urine and saliva by
HPLC and UV-detection (internal standard, iso-
propylamino antipyrine).[8.1O] The detection limit
was 0.1 mglL; within-day precision varied between

© Adis International Limited. All rights reserved. Clin. Pharmacokinet. 28 (3) 1995
218 Levy et a/.

Conjugates

Dipyrone

Other metabolites

Other metabolites

Other metabolites

Fig. 1. Biotransformation of dipyrone in humansPI

1.5 and 3.6%andday-to-dayprecision between2.4 of 1g dipyrone as tablets, drops, suppositories, in-

and6.7%.[8] tramuscular and intravenous injection (tables I to
IV).[19] The bioavailability of MAA was 85% for

1.2 Absorption
Dipyrone is rapidly hydrolysed to MAA in the
gastric juice and is almost completely absorbed in
this form. f 11,12] The pharmacokinetics of MAA and
its secondary metabolites were studied in healthy
volunteers after the administration of a single dose
the tablets, 89% for the drops, 54% for the supposi-
tories and 87% for the intramuscular injection. Al-
though the results came from 2 separate sets of
data, it was suggested that following intramuscular
injection, peak MAA concentrations (C max ) and the
time taken to achieve Cmax values (t max ) did not differ
markedly from the oral formulations, whereas

© Adis International Lirnited. All rights reserved . Clin. Pharrnocokinet. 28 (3) 1995
Pharmacokinetics of Dipyrone 219

Table I. Pharmacokinetic characteristics of 4-methyl-amino-antipyrine (MAA) after administration of a single dose of dipyrone in heaijhy male,
unless specified, individuals. Results are expressed as mean [± SO], unless specified differently

Dose Route of No. of Cmax tmax AUC CUF VdlF h"p Ae CLR Reference
(g) administration patients a (mg/L) (h) (mg/Loh) (ml/min) (L) (h) ('Yo dose) (ml/min)
(dosage form)
0.75 PO(T) 15 10.6 1.4' 48.7 180 41.3 2.7 2.2 4 13
[2.3] [0.3] [14.9] [67] [7.9] [1.1] [1.4] [2]
1.5 PO(T) 15 20.5 1.7 115.5 165 41.2 2.9 2.9 4
[3.8] [0.4] [45.9] [74] [8.3] [0.8] [1.4] [3]
3.0 PO(T) 15 41.4 2.0 314.7 110' 38.3 3.7' 4.0' 4
[5.7] [0.5] [82.9] [27] [4.9] [0.7] [1.3] [2]
1.0 PO(T) 9 12.2 1.3 64.5 170 43.8 2.7 3.0 5 14
[1 .4] [0.4] [13.4] [37] [4.7] [0.5] [1.0] [2]
1.0 PO(T) 12 12.3 1.5 NO 3.97 1.19 2.6 NO NO 15b
[1.1] [0.1] [0.38]C [0.13]d [0.2]
1.0 PO(T) 12 10.3 1.5 76.3 NO NO 2.6 NO NO 16
[fasting] [3.1] [0.4] [27.8] [0.8]
1.0 PO(T) 12 9.7 1.9' 95.1 NO NO 2.5 NO NO
[with food] [2.8] [0.4] [34.1] [0.6]
1.0 PO(T) 12 10.0 1.6 75.4 3.6 NO 3.5 NO NO 17
(slow [0.6] [0.6] [32.9] [1.1]" [0.8]
acetylators,
5 female)
1.0 PO(T) 11 11 .0 1.2 71 .3 4.4 NO 3.1 NO NO
(rapid [3.0] [0.4] [30.9] [2.0]" [1.1]
acetylators,
7 female)
1.0 PO(T) 6 13.9 1.3 69.1 NO NO 2.6 NO 6 18
[5.3] [0.5] [40.8] [0.6] [1]
1.0 IV 6 51.3 NO NO 2.8 NO 28
[31.1] [0.6] [17]
1.0 PO(T) 12 17.3 1.4 80.9 146 42.9' 3.2 3.4 3 19
[7.5] [0.5] [34.1] [54] [11.6] [0.9] [1.2] [1]
1.0 POtS) 12 14.3 1.2 69.1 164 45.4' 3.2 2.6 4
[2.9] [0.5] [19.6] [61] [8.5] [0.7] [1 .0] [1]
1.0 IV 12 71.2 150 34.0 3.2 16.6 4
[13.7] [30] [6.2] [0.8] [4.6] [1]
1.0 IV 12 67.8 161 33.5 2.8 22.1 4 19
[16.1] [44] [9.8] [1.1] [5.7] [2]
1.0 1M 12 11.4 1.7 64.1 168 55.0' 3.1 14.0 10
[3.1] [0.7] [14.8] [36] [9.3] [1.0] [4.8] [4]
1.0 Rectal 12 6.1 2.4 47.0 256' 100.0' 4.1 5.0 6
[1 .9] [1.2] [22.2] [89] [29.9] [3.2] [1 .8] [2]
a For a given parameter the actual number may be less, if precise calculation was impossible.
b ± SEM instead of SO.
c CL given as mllmin/kg lean body mass.
d Vd/F given as L1kg lean body mass.
e CL given as mllmin/kg.
Abbreviations and symbol: Ae =amount excreted in urine; AUC =area under the plasma concentration-time-curve; CLR = renal clearance;
Cmax = maximum plasma concentration; CUF = apparent total body clearance after oral administration where F represents bioavailability
(including extent of metabolite formation) ; 1M =intramuscular administration; IV =intravenous administration; NO =not determined or reported;
PO =oral administration S =oral solu1ion; !max =time to maximum plasma concentration; VdlF =apparent oral volume of distribution; h,p =terminal
elimination half-life; T =tablet; , =significantly different from comparison groups, p S 0.05.

© Adis International Limited. All rights reseNed. Clln. Pharmacokinet. 28 (3) 1995
220 Levy et al.

Table II. Pharmacokinetic characteristics (mean ± SO) of 4-amino-antipyrine (AA) after a single dose of dipyrone in healthy individuals
Oose Route of No. of Cmax tmax AUC CUF h2~ Ae CLR Reference
(g) administration patientsa (mg/L) (h) (mg/Loh) (mllmin) (h) (%dose) (ml/min)
(dosage form)
0.75 PO(T) 15 1.0 3.4 10.6 1064" 4.1"" 5.2 32 13
[0.5] [1.5] [7.9] [655] [1.3] [3.9] [20]
1.5 PO(T) 15 2.3 4.6 29.0 805 4.8 6.4 31
[1.1] [2.3] [20.2] [531] [2.1] [4.7] [12]
3.0 PO (T) 15 4.7 6.9" 71.7 652 5.4 9.2" 34
[2.7] [2.4] [48.4] [430] [1.7] [7.2] [17]
1.0 PO(T) 9 1.5 4.4 16.9 820 3.7 6.1 38 14
[0.8] [0.9] [9.7] [501] [1.3] [2.9] [13]
1.0 PO(T) 12 (slow 2.7 6.7 45.6 NO 5.5 NO NO 17
acetylators, [0.6] [2.1] [12.7] [1 .0]
5 female)
1.0 PO(T) 11 (rapid 1.6" 3.2" 16.7" NO 3.8" NO NO
acetylators, [0.7] [1 .1] [4.7] [1.2]
7 female)
1.0 PO(T) 12 1.9 4.8 33.5 459 8.3 9.1 29 19
[0.8] [2.1] [19.6] [383] [3.5] [4.7] [12]
1.0 POlS) 12 1.7 5.1 30.4 390 9.9 8.9 30
[0.6] [2.5] [13.0] [208] [3.5] [4.1] [9]
1.0 IV 12 1.5 4.8 22.9 600 8.6 6.3 28
[0.8] [2.5] [11.3] [438] [4.6] [3.6] [8]
1.0 IV 12 1.6 3.1 20.9 508 6.2 8.1 41 19
[0.4] [3.2] [6.2] [176] [2.2] [3.7] [15]
1.0 1M 12 1.6 5.5 25.1 459 6.7 8.8 36
[0.3] [2.2] [11.1] [194] [2.0] [4.1] [12]
1.0 Rectal 12 1.4 6.0 21.2 506 6.7 8.1 43
[0.4] [2.2] [7.4] [175] [2.6] [3.7] [18]
a For a given parameter the actual number of patients may be less, if precise calculation was impossible.
Abbreviations and symbols: Ae = amount excreted in urine; AUC = area under the plasma concentration-time-curve; CLR = renal
clearance; C max = maximum plasma concentration; CUF = apparent total body clearance after oral administration where F represents
bioavailability (including extent of metabolite formation); 1M = intramuscular administration; IV = intravenous administration; NO = not
determined or reported; PO = oral administration; S = oral solution; t max = time to maximum plasma concentration; tll.1~ = terminal elimination
han-Jije; T = tablet; " significant difference between comparison groups, p S 0.05; "" significant difference between 0.75 and 3.0g doses, p S 0.05.

absorption from suppositories was delayed and in-
complete (see tables I to IV).
As shown in table I, a linear relationship was
found between dose and C max of MAA following the
administration of film-coated tablets of dipyrone in
a crossover study.[13] The tmax was reached between
1.4 and 2.0 hours following oral doses of 0.75, 1.5
and 3.0g. These results tend to indicate that
dipyrone is absorbed by a nonsaturable process.
In 12 healthy volunteers given a single Ig dose
of dipyrone, taking the tablets with food resulted
in a significant, but small, delay in the mean tmax of
MAA.[16] There was no significant difference in
area under the plasma concentration-time curve
(AUC) or C max between fasting and nonfasting
conditions. Small differences were noted in the ab-
sorption rate constant (ka ) between the fasting
(0.96 ± 0.35 hours) and the nonfasting (1.58 ± 0.92
hours) states (p < 0.05).[16]
1.3 Distribution
None of the major metabolites of dipyrone is
extensively bound to plasma proteins.[20] The mean
plasma protein binding, as determined by ultra-
filtration in an ex vivo study, was 57.6% for MAA,
47.9% for AA, 17.8% for FAA and 14.2% for AAA.
The correlation between unbound and total plasma
concentration was linear for each of the metab-

© Adis International Umited. All rights reselVed. Clin. Pharmacokinet. 28 (3) 1995
Pharmacokinetics of Dipyrone 221

olites. No association was found between total
plasma protein concentration and the extent of
binding. The greater binding affinity for MAA and
AA relative to FAA and AAA relates to the physico-
chemical nature of these substances such as lipid
solubility.
The mean volume of distribution (V d) of MAA in
healthy volunteers after intravenous administration
of dipyrone (table I) is 33.5L.[l9J In another study,
following oral administration, the mean apparent Vd
(i.e. VdIF)ofMAAwas 1.19 L/kgleanbodymass.[ISJ
Taking into account protein binding, this value is con-
sistent with the hydrophilic properties of MAA and
the lack of extensive tissue binding.
The transfer of dipyrone metabolites to breast
milk was determined in 8 nursing women follow-
ing a single oral dose of the drug. A good correla-
tion (p < 0.005) was found between concentrations
in the plasma and breast milk of MAA (r = 0.89),
AA (r = 0.93), FAA (r = 0.98) and AAA (r =0.96).
Mean (± SD) milk to plasma concentration ratios
were as follows: MAA 1.37 ± 0.28; AA 1.15 ± 0040;
FAA 1.03 ± 0.09; and AAA 0.97 ± 0.24J21J The
concentration-time profiles of the metabolites in
breast milk were studied in 2 nursing mothers. In
one mother (a slow acetylator), 4 hours after drug
administration the milk concentration of MAA,
AA, FAA and AAA were 5.8, 0.98, 3.5 and 0.8

Table Ill. Pharmacokinetic characteristics of 4-acetyl-amino-antipyrine (AAA) after a single dose of dipyrone in healthy individuals
Dose Route of No. of patients' C max tmax AUC CUF t'h~ Ae CLR Reference
(g) administration (mg/L) (h) (mg/L.h) (mllmin) (h) (% dose) (ml/min)
(dosage form)
0.75 PO(T) 15 2.1 11.1 50.3 201 8.8 24.0 47 13
[1.1] [4.0] [19.4] [81] [1.9] [5.8] [13]
1.5 PO(T) 15 4.7 13.1 120 173 9.4 22.2 36
[2.8] [5.8] [51] [61] [1.4] [11.4] [15]
3.0 PO(T) 15 8.0 17.9' 222 186 8.6 26.8 45
[4.6] [6.9] [95] [82] [1.3] [10.7] [17]
1.0 PO(T) 9 1.8 15.0 51.4 281 9.5 26.4 61 14
[0.6] [6.4] [15.9] [90] [1.5] [8.2] [8]
1.0 PO(T) 12 1.6 16.1 62.8 ND 11.2 ND ND 17
(slowacetylators, [0.4] [5.1] [25.6] [2.1]
5 female)
1.0 PO(T) 11 4.4' 10.0' 125.8' ND 9.9 ND ND
(rapid acetylators, [1.1] [2 .6] [27.2] [2.2]
7 female)
1.0 PO(T) 12 1.8 14.0 45.8 266 10.3 21.2 64 19
[0.8] [6.5] [11.4] [56] [2.5] [6.7] [16]
1.0 PO(S) 12 1.8 11.8 46.3 277 10.6 21.0 59
[1.0] [4.6] [17.0] [79] [3.0] [8.3] [11]
1.0 IV 12 1.4 13.0 31.3 412 11.1 15.2 66
(0.8] [5.8] [11.4] [132] [3.4] [4.7] [11]
1.0 IV 12 1.6 17.3 46.3 312 12.4 16.8 62 19
[1.1] [7.3] [24.8] [130] [3.7] [6.0] [18]
1.0 1M 12 1.8 18.3 48.8 269 11.7 19.3 60
[0.9] [6.2] [20.2] [88] [2.1] [7.5] [15]
1.0 Rectal 12 1.7 19.7 44.3 301 12.8 17.1 70
[0.8] [7.0] [15.5] [127] [4.8] [6.6] [17]
a For a given parameter the actual number may be less, if precise calculation was impossible.
Abbreviations and symbol: Ae =amount excreted in urine; AUC =area under the plasma concentration-time-curve; CLR = renal clearance;
C mex = maximum plasma concentration; CUF = apparent total body clearance after oral administration where F represents bioavailability
(including extent of metabolite formation); 1M =intramuscular administration; IV =intravenous administration; ND =not determined or reported;
PO =oral administration S =oral solution; t max =time to maximum plasma concentration; VdlF =apparent oral volume of distribution; tll2~ =terminal
elimination half-life; T = tablet; , = significantly different from comparison groups, p " 0.05.

© Adis International Limited. All rights reserved. Clin. Pharmacoklnet. 28 (3) 1995
222 Levy et al.

Table IV. Pharmacokinetic characteristics (mean ± SO)014-formyl-amino-antipyrine (FAA) aiter a single dose of dipyrone in healthy individuals
Oose Route of No. of patients' Cmax lmax AUC CUF t'f.!~ Ae CLR Reference
(g) administration (mglL) (h) (mglLoh) (mllmin) (h) (% dose) (mllmin)
(dosage form)
0.75 PO(T) 15 1.6 6S 34.4 268 9.6 15.8' 42 13
[0.5] [2.3] [11.5] [100] [1.7] [6.2] [14]
1.5 PO(T) 15 2.5 8.0 73.3 347 10.0 12.7 39
[0.9] [2.2] [40.4] [217] [2.7] [6.1] [16]
3.0 PO(T) 15 3.1 8.9 81 .0 516' 10.3 11.0 48
[1.3] [2.1] [40.1] [334] [2.2] [4.7] [23]
1.0 PO(T] 9 2.4 5.8 52.1 221 11.2 22.7 49 14
[0.5] [1.3] [6.3] [28] [1.5] [4.3] [5]
1.0 PO(T) 12 1.8 7.7 48.1 NO 10.0 NO NO 17
(slowacetylators, [0.4] [2.6] [7.9] [1.4]
5 female)
1.0 PO(T) 11 2.5 6.6 57.9 NO 10.1 NO NO
(rapid acetylators, [1.1] [2.3] [16.9] [2.1]
7 female)
1.0 PO(T) 12 1.8 7.0 38.7 296 10.6 16.8 53 19
[0.3] [2.5] [7.4] [72] [2.2] [2.1] [12]
1.0 PO(S) 12 1.8 6.7 38.3 304 10.6 16.1 51
[0.5] [1.6] [8.3] [90] [2.3] [3.1] [13]
1.0 IV 12 1.4 7.2 27.7 414 9.7 13.0 57
[0.3] [2.3] [5.7] [93] [2.4] [2.4] [10]
1.0 IV 12 1.4 8.2 36.9 334 13.1 14.2 44 19
[0.5] [2.9] [15.3] [111] [2.4] [4 .2] [17]
1.0 1M 12 1.4 10.7 39.4 330 12.8 13.5 45
[0.4] [3.7] [12.1] [205] [2.9] [4.1] [10]
1.0 Rectal 12 1.4 9.7 42.2 289 15.3 14.5 34
[0.4] [2.8] [11 .0] [132] [3.9] [4.0] [13]
a For a given parameter the actual number may be less. if precise calculation was impossible.
Abbreviations and symbols: Ae = amount excreted in urine; AUC = area under the concentration-time-curve; CLR = renal clearance;
Cm,x =maximum plasma concentration; CUF =apparent total body clearance aiter oral administration where F represents bioavailability (including
ex1ent of metabolite formation); 1M = intramuscular administration; IV =intravenous administration; NO =not determined or reported; PO = oral
administration; S = oral solution; tm,x =time to maximum plasma concentration; t l",~ =terminal elimination half-life; T =tablet; , statistically
significant difference between comparison groups, p $ 0 .05.

mg/L, respectively. In a second mother (a rapid
acetylator) the milk concentrations of MAA, AA,
FAA and AAA were 3.7, 1.3,4.3 and 2.6 mg/L, re-
spectively. At 48 hours after drug administration,
MAA and AA were undetectable and FAA and AAA
were 0.2 and 0.3 mg/L for the first mother and 0.4 and
0.7 mg/L, respectively, for the second mother.
Passage of dipyrone metabolites into the cerebro-
spinal fluid (CSF) is presently under investigation.
Our own unpublished preliminary results indicate
that all 4 metabolites cross the blood-brain barrier.
MAA, AA, FAA and AAA are all found in saliva,
and their concentrations correlate well (p < 0.001)
with their respective plasma concentrations (r = 0.81,
0.62, 0.83 and 0.91. respectively).l7,IO) Concen-
trations of FAA and AAA in the saliva were similar
to their respective plasma concentrations. while
those of MAA and AA were lower than their plasma
concentrations. The saliva: plasma concentration
ratio is also dependent on the sampling time. These
differences in the relationship between saliva and
plasma concentrations for the 4 metabolites can be
explained by the differing plasma protein binding
and the pKa values of the metabolites.
1.4 Metabolism and Elimination
In vitro, dipyrone is degraded with a half-life of
16 minutes.[12) After intravenous administration.
unchanged dipyrone may be present in plasma for

© Adis Internationallirnited. All rights reserved. Clin. Pharrnacokinet. 28 (3) 1995

Pharmacokinetics of Dipyrone 223

a very short period of time, whereas after oral ad- 10 Slow acetylators (n = 12)

ministration of the drug it cannot be detected in DMAA

plasma or urine. The primary hydrolysis product, eAA
OAAA
MAA, is metabolised, possibly in the liver, by de- & FAA
methylation to AA and either directly or via AA to
FAA (see fig. 1). The specific cytochrome P450
::J
isoenzymes involved in this metabolism have not 0,

yet been identified. The acetylation of AA to AAA

.sc
0
has been demonstrated to result from the activity ~
C 0.1
of the hepatic polymorphic N-acetyl-transferase Q)
0
c
0 10
systemJl7] This explains the marked interindivid- 0
co
ual differences in AAA concentrations first re- E
en
co
ported by Goromaru et alJ22] c::
The mean plasma concentration-time curves of
the metabolites in individuals who are rapid or
slow acetylators, following single dose adminis-
tration of dipyrone Ig, are shown in figure 2 (see
also tables I to IV). MAA, the product of the non-
enzymatic hydrolysis of dipyrone in the intestine, O.ll+-.---r-..,---,---,--,--r-.---r---,
is the first of the major metabolites of dipyrone to o 5 10 15 20 25 30 35 40 45 50
achieve Cmax values and then becomes the first me- Time (h)

tabolite to be nondetectable in the plasma. Next to

reach C max values are AA and FAA. AAA and FAA
are the major metabolites present in the urine. They
are still detectable in the plasma of healthy volun-
teers 48 hours after administration of the drugJl6]
In a more recent study,[23] the pharmacokinetic pa-
rameters of dipyrone metabolite formation and
elimination obtained in 9 slow and 3 rapid acetyl-
ators are summarised in table V. Mean tY2 values for
MAA, FAA and AAA were similar in both slow and
rapid acetylators, while a significant difference
was found for AA - tl/2 of 8.1 hours for slow and
3.7 hours for rapid acetylators.
The pharmacokinetics of dipyrone metabolites
were also studied in 15 healthy volunteers follow-
ing administration of single oral doses of 0.75, 1.5
or 3g [tables I to IV).[l3] These tables include val-
ues for apparent clearance (CLlF) of all 4 metabo-
lites. It should be noted that 'F' adjusts for both
bioavailability and metabolite formation; never-
theless CLIP is considered to be a clinically useful
parameter since it is a predictor for average steady-
state concentrations. The tl/2 of MAA increased and
CLIP decreased significantly with the dose. AUC
Fig. 2. Concentration-time-profiles of dipyrone metabolites (4-
methyl-amino-antipyrine: MAA; 4-amino-antipyrine: AA; 4-acetyl-
amino-antipyrine: AAA; and 4-formyl-amino-antipyrine: FAA) in 12
slow and 11 rapid acetylators.[171Data are given as means ± SEM.
increased more than dose-proportionally; there
was a 2.7-fold increase in AUC when the dose was
doubled from 1.5 to 3g. In addition, there was a
much less than expected increase in the AUC of
FAA (AUC increased by only 10% when the dose
was doubled. The tY2 values for AA increased when
the dose of dipyrone was increased from 0.75 to
3.0g; AUC increased nonlinearly. CLIP of FAA be-
came larger with increasing doses, whereas the
pharmacokinetics of AAA were essentially un-
changed with increasing doses.
The nonlinear pharmacokinetics observed for
some metabolites point to the saturability of the
metabolic pathways. There were no significant be-
tween-dose differences in renal clearance for any
of the major metabolites. For the doses studied in
healthy volunteers the changes observed are un-
likely to be clinically significant.

© Adis International Limited. All rights reserved. Clin. Pharmacokinet. 28 (3) 1995
224 Levyet at.

Table V. Mean (± SEM) pharmacokinetic characteristics of dipyrone metabolites in 9 slow and 3 rapid acetylators after oral administration of
19 dipyronel231
Acetylator t'f.1P Vd AUC Ae CUF ClR ClNR ClM
status (h) (Ukg) (mg/l-h) (mg) (ml/minlkg) (ml/min/kg) (ml/min/kg) (mllmin/kg)

MAA
Slow 2.7 0.59 58.8 22.6 2.6 0.10 2.5
[0.2) [0.05) [6.4) [2.7) [0.3) [0.02) [0.2)
Rapid 2.5 0.55 50.6 23.0 2.8 0.11 2.7
[0.5) [0.03) [8.9) [1 .9) [0.7) [0.03) [0.7)

AA
Slow 8.1 23.8 54.7 0.55 0.25
[1.1) [2.6) [5.7) [0.05) [0.03)
Rapid 3.7* 5.0' 14.3' 0.62 0.10'
[0.6) [0.6) [0.6) [0.03) [0.02)

AAA
Slow 10.6 29.9 102.3 0.87 0.78
[0.9) [4.9) [10.0) [0.07) [0.09)
Rapid 10.8 67.0' 240.0' 0.76 7.53"
[1.1) [1.4) [22.7) [0.05) [1.23)

FAA
Slow 10.9 30.1 99.0 0.78 0.39
[1 .6) [2.3) [7.5) [0.05) [0.05)
Rapid 10.8 27.5 89.1 0.69 0.49
[1.5) [3.5) [15.2) [0.06) [0.11)
Abbreviations and symbol: Ae = amount of metabolite excreted in the urine; CUF = apparent total body clearance after oral administration
where F represents bioavailability (including the extent of metabolite formation); CLNR = non-renal clearance; ClM = clearance of metabolite;
ClR = renal clearance; t1f.!P = terminal elimination half-life; Vd = volume of distribution; "= statistically significant difference between comparison
groups, p < 0.05.

In a multiple-dose study, the pharmacokinetic plained by a reduction in the metabolic clearance

properties of the 4 dipyrone metabolites were de-
termined in healthy volunteers following a single
Ig oral dose and compared with results obtained
after administration of Ig 3 times daily for 7 days
(22 doses, including a final dose on day 8) [table
VI].l14] Significant changes in several pharmaco-
kinetic parameters occurred for MAA, AA and
FAA during multiple dose administration. As illus-
trated in figure 3, mean plasma concentrations of
MAA and AA during multiple administration were
approximately 1.3- to 2-fold higher than those pre-
dicted after single-dose administration. In contrast,
plasma concentrations of FAA decreased by 66% and
AAA phannacokinetics remained unchanged (fig. 3).
Following multiple administration of dipyrone,
relative CLiF of MAA decreased and its tl/2 and
MRT increased. The CLiF of AA decreased, while
that of FAA increased. These findings, together
with those of the dose-linearity study[13] can be ex-
of MAA. This could be a direct result of enzyme
saturation or product inhibition resulting in either
an increased formation of AA due to a shift of MAA
metabolism from FAA to AA or in a decrease of
conversion of AA to FAA; these interpretations are
consistent with the observed increase in the CLIF
of FAA with increasing doses. However, other
changes in the distribution or elimination processes
of any of the 4 metabolites cannot be excluded.
A significant difference was found in the rate of
metabolism of AA to AAA between slow and rapid
acetylators. Similar differences were noticed for
the urinary excretion.[23]
The mean percentage of the dose found in the
urine following the oral administration of 19 of
dipyrone is 2 to 4% for MAA, 5 to 9% for AA, 21
to 27% for AAA and 11 to 23% for FAA (tables I
to IV). Renal clearance of the 4 metabolites is on
average between 3 and 70 mllmin (0.18 to 4.2 L/h)

© Adis International Limited. All rights reserved. Clin. Pharmacokinet. 28 (3) 1995
Pharmacokinetics of Dipyrone 225

[tables I to IV]. Thus, tubular secretion most likely
is not involved in renal excretion of dipyrone. It
was shown that the cumulative urinary excretion
of MAA, following administration of a Ig oral
dose, was much less than after administration by
the intravenous route.[I8,19] It was suggested that
after intravenous administration some of the un-
changed dipyrone is excreted into the kidneys
where it is converted to MAA.[18] Another way to
explain the finding could reside in a supposed
process of intestinal N-demethylation of MAA.
1.5 Acetylation Phenotyping
It was shown that the acetylation of AA to AAA
correlates with that of dapsone, thus, consistent
with the function of the polymorphic N-acetyl-
transferase system (fig. 4))17] The AAA : AA
concentration ratio measured in plasma or urine
was demonstrated to be a reliable discriminatory
index between slow and rapid acetylators.[23]
Thus, measuring these metabolites in plasma or
urine can be used to determine acetylation pheno-
type (fig. 4).
Similar bimodality is evident from the sali-
vary AAA : AA concentration ratios. Six hours
after dipyrone ingestion, the saliva AAA : AA
ratio was 2.6 ± 0.6 (n = 7) in slow acetylators
and 15.3±3.1 (n=3) in rapid acetylators, and
there was a significant difference between
groups (p < 0.02))10]

Table VI. Pharmacokinetic characteristics of dipyrone metabolites after single- and multiple-dose administration in healthy individuals. [141 Nine
healthy male individuals received 1g dipyrone (2 film-coated tablets of 0.5g) as a single-dose followed by 3 doses of 1g daily for 7 days after
a washout period of 6 days. On day 8 of the multiple-dose period only the morning dose was given, and blood and urine samples were taken
as after the first single-dose. Results are expressed as mean [± SD)
Phase Cmax tmax AUC' CUF Vd/F tlf.1~ MT Ae b CLR
(mg/L) (h) (mg/L.h) (ml/min) (L) (h) (h) (% dose) (ml/min)

MAA
Single-dose 12.2 1.3 64.5 170 43.8 2.7 4.4 3.0 5
[1.4) [0.4) [13.4) [37) [4.7) [0.5) [0.8) [1.0) [2)
Multiple-dose 16.5 1.3 81.8' 132' 43.2 3.3' 5.6' 4.2' 5
[2.6) [0.5) [18.4) [29) [5.8) [0.4] [0.7) [1.1) [2)

AA
Single-dose 1.5 4.4 16.9 820 3.7 8.6 6.1 38
[0.8) [0.9) [9.7] [501) [1.3) [1.8) [2.9) [13)
Mu[tiple-dose 4.9 2.8 33.0- 479- 3.7 9.3 8.9- 40
[2.7) [1.2) [18.6) [388) [0.5) [1.8) [4.0] [8)

AAA
Single-dose 1.8 15.0 51.4 281 9.5 24.1 26.4 61
[0.6) [6.4) [15.9] [90) [1.5) [2.9) [8.2) [8)
Multiple-dose 7.1 1.5 46.5 300 8.5 23.8 27.7 73-
[3.3] [2.0) [22.4) [120] [1.8] [4.2] [11.2) [9)

FAA
Single-dose 2.4 5.8 52.1 221 11.2 19.6 22.7 49
[0.5) [1.3] [6.3) [28) [1.5) [2.1] [4.3) [5]
Multiple-dose 2.7 1.6 17.6' 662' 9.4- 20.3 10.1' 59
[0.8) [1.6] [4.9] [173) [1.9) [3.6] [1.8] [9)
a AUC extrapolated to infinity for single-dose and calculated during the dosage interval for multiple-dose.
b Ae to 144 hours for single-dose and during dosage interval for multiple-dose.
Abbreviations and symbol: Ae = amount of metabolite excreted in the urine; AUC = area under the plasma concentration-time curve;
C max = maximal plasma concentration; CUF = apparent total body clearance after oral administration where F represents
bioavailability (including the extent of metabolite formation); CLR = renal clearance; MT = mean residence time; t'f.1~ = terminal elimination
half-life; tmax = time taken to achieve maximal plasma concentration; VdlF = apparent volume of distribution after oral administration; - = statistically
significant difference between comparison groups, p < 0.05.

© Adis International Limited. All rights reserved. Clin. Pharmacokinet. 28 (3) 1995
226 Levy et a/.

100 10
MAA AA

•• ••
:::J
0, •• •• ft
•
§. 10
c
0
.~

cCD
()
C
0
U
•
0.1 0.1
0 24 48 72 96 120 144 168 192 0 24 48 72 96 120 144 168 192

100 AAA 10

:::J
0,
§. 10
c
0
•
~
C
<I>
()
c
0
U

0.1 0.1
0 24 48 72 96 120 144 168 192 216 240 0 24 48 72 96 120 144 168 192 216 240
Time (h) Time (h)

Fig. 3. Mean plasma concentrations of 4-methyl-amino-antipyrine (MAA), 4-amino-antipyrine (AA), 4-acetyl-amino-antipyrine (AAA)
and 4-formyl-amino-antipyrine (FAA) during multiple administration of dipyrone.(14) Trough concentrations and concentrations after
the last dose of the multiple-dose administration phase are given by points; the lines indicate the multiple-dose concentration-time
profiles predicted from single-dose data.

2. Pharmacokinetics
in Special Populations
2.1 Influence of Age,
Gender and Ethnic Origin
It was reported that children (1 to 11 years old)
eliminated dipyrone metabolites more rapidly than
did adults.[24] The interpretation of these findings
is hampered by the fact that these investigators
used a nonspecific spectrophotometric assay that
could not discriminate between the various me-
tabolites of dipyrone. In practice, the dosage of
dipyrone for infants and children is governed by
bodyweight.
The pharmacokinetics of MAA were studied in
9 elderly (73 to 90 years old) individuals (6 female
and 3 male) who were free from any major sys-
temic disease. Results were compared with those
reported in 12 young (21 to 30 years old), male,
healthy volunteers. Mean (± SEM) tl/2 in the elderly
and young were 4.5 ± 0.5 and 2.6 ± 0.2 hours, re-
spectively. The CLIF of MAA decreased by 33% in
the elderly compared with the young and correlated
well with creatinine clearance. f15] However, it is
also possible that impaired hepatic metabolism
largely contributes to the prolonged MAA elimina-
tion in the elderly, since a more recent study[25]
could not detect any definite relationship between
creatinine clearance and MAA clearance.
No gender difference in the pharmacokinetics of
MAA was seen in a single-dose study (slow acetyl-
ators: 7 male and 5 female; rapid acetylators: 4
male and 7 female).f 17 ] In an unpublished drug in-

© Adis Internotionollimited. All rights reserved. Clin. Phormocokinet. 28 (3) 1995

Pharmacokinetics of Dipyrone 227

teraction study in 6 healthy male and 6 healthy fe- 1.4 • Slow acetylators
• •
male individuals, however, slower elimination of
MAA and AA was noticed in females (W. Scholz,
B. Rosenkranz, personal communication). The
question of gender difference after multiple admin-
'W 10
<f)

'"
1.2
o Rapid acetylators

•
• •
..
•
•
S08
istration of the drug remains unanswered.
<C .
<C
~ 0.6
•
In a study of dipyrone metabolite kinetics in 10 <C
0
Black and 10 White healthy volunteers, no statis- iii 0.4
r = 0.895
a: p <0.0005
tically significant differences were detected after
normalisation for the different bodyweights of the 0.2
•
individuals (B.H. Meyer, B. Rosenkranz, personal 0.0 •
communication). No pharmacokinetic studies of di- 0.0 0.2 0.4 0.6 0.8 10
pyrone in other ethnic groups have been published. MADDS/Dapsone

2.2 Pregnancy
10
•
The pharmacokinetics of dipyrone during preg- m
8
• •
nancy have been investigated, but the results are "
.;:
2- 6
difficult to interpret because a nonspecific assay <C
<C
was used.l 26 ] Decreased excretion of dipyrone me- ~
<C
<C 4
tabolites in the first 9 hours after oral administra- 0
~ r = 0.968
tion[26] and a prolonged tv,[27] have been reported. a: p <0.0005
2
In another study,[ 28 1 the tv, of the metabolites of
dipyrone was similar in pregnant and nonpregnant
patients. a
a 2 3 4 5 6
Ratio AANAA (plasma)
2.3 Liver Disease 10 r = 0.995
p <0.0005
The pharmacokinetic parameters of the metabo-
8
lites of dipyrone were determined following the
m
administration of a single 1.0g dose of dipyrone to "
.;:
2- 6
12 individuals with cirrhosis of the liver.[29] These <C
results were compared with those obtained in 12 ~
<C
<C 4
healthy individuals (table VII). The mean C max of 0
.~
MAA was similar in the 2 groups. Significant dif- a: r = 0.995
ferences were found between the cirrhotic and 2 P <0.0005

healthy individuals for tmax, tl/2 and CLiF. The latter

difference was largely due to differences in non-
renal clearance; however, renal clearance was
also significantly diminished in the patients with
liver disease. The mean plasma concentration-time
curves for MAA in the patients with hepatic cirrho-
sis and in healthy individuals are shown in figure 5.
In the patients with liver disease, linear correla-
tions (p < 0.05) were found between tl/2 of MAA
and the following: serum albumin (r =0.71), as-
partate aminotransferase (r =0.77), alanine amino-
a
a 10 20 30 40
Time (h)
Fig. 4. Top: Correlation between the ratio of plasma concentrations
of 4-acetyl-amino-antipyrine (AAA) to 4-amino-antipyrine (AA) [2
hours after administration of 19 dipyronel and the ratio of plasma
concentrations of the acetylated product of dapsone (MADDS) to
those of dapsone in plasma (3 hours after administration of dapsone
0.1 g) in 23 individuals.!'7] Middle: Correlation between the AANAA
ratio in plasma (6 hours after oral administration of dipyrone) and the
AANAA ratio in 24h urine.!23] Bottom: Ratio of AANAAconcentration
in urine at various time points following oral administration of 19
dipyrone to slow and rapid acetylators.[23]

© Adis International Limited. All rights reserved. Clin. Pharmacokinet. 28 (3) 1995
228
Table VII. Mean (± SEM) pharmacokinetic characteristics of MAA
in patients with liver disease and healthy individuals (M. Levy, E.
Zylber-Katz, personal communication)
Parameter Patients with liver Healthy individuals
disease (n = 12) (n = 12)
Cma,(mg/L) 9.6 ± 1.2 11.S± 1.1
tma, (h) 3.0 ± 0.6 1.6±0.1'
tlr"p (h) 10.6 ±2.0 2.7 ±0.2'
Ae (mg) 39.8 ± 7.8 22.8 ± 2.0'
CUF (ml/min/kg) 1.12 ± 0.24 2.68 ±0.23'
CLR (mllmin/kg) O.OS ± 0.01 0.1 ±0.01'
CLNR (mllmin/kg) 1.07 ± 0.24 2.S8 ± 0.22'
Abbreviations and symbol: Ae = amount of metabolite excreted in
the urine; Cma, = maximal plasma concentration; CUF = apparent
total body clearance after oral administration where F represents
bioavailability (including the extent of metabol ite formation);
CLR = renal clearance; CLNR = nonrenal clearance; t1/,P = terminal
elimination half-life; tma, = time taken to achieve maximal plasma
concentration; , indicates statistically significant difference between
comparison groups.
transferase (r = 0.67), lactic dehydrogenase (r = 0.79),
alkaline phosphatase (r = 0 .76) and total biliru-
bin (r = 0.89) levels and the prothrombin ra-
tio (r = 0.64)J291Close to a 3-fold increase in tmax
and tl/2 were noted for FAA in the patients with
cirrhosis, and reduced metabolite formation was
also observed. The appearance of AA was signif-
icantly delayed in these patients and the acetyla-
tion of AA to AAA was significantly impaired.
The t max and tY2 of AAA were doubled in the
patients with cirrhosis compared with values
in healthy individuals (E. Zylber-Katz, personal
communication).
These results show that dipyrone metabolism is
impaired in patients with liver cirrhosis due to a
reduction in both the demethylation-oxidation and
acetylation pathways. When the urinary excretion
of the 4 metabolites was accumulated, levels of uri-
nary excretion in patients with cirrhosis were only
70% of those in controls. Possible explanations
may be altered bioavailability or increased forma-
tion of another non detected metabolite. Decreased
renal clearance in patients with cirrhosis, as ob-
served for MAA, is well known for endogenous
substances as well as for drugs.
© Adis International Limited. All rights reserved.
Levy et al.
2.4 Kidney Disease
The pharmacokinetics of dipyrone were stud-
ied in 24 patients with creatinine clearance val-
ues between 4 and 157 mllmin (0.24 and 9.42
Llh) after oral administration of a I g dose.f 251
While renal clearance of all 4 metabolites de-
creased in linear relationship to creatinine clear-
ance, CLiF of MAA and AA remained unaltered
in patients with different degrees of renal impair-
ment (fig. 6). This may be explained by the fact
that the main pathway of elimination for these
2 metabolites is hepatic metabolism.
CLiF of AAA and FAA is linearly related to cre-
atinine clearance. It should be noted that the esti-
mated CLiF of AAA in anuric patients is still 31
ml/min (1 .9 L/h), whereas that of FAA is not sig-
nificantly different from 0 mllmin (0 Llh). This is
consistent with the metabolic scheme described
(fig. I), which indicates that FAA is a true end-
metabolite, whereas AAA may undergo further
metabolism. The mean (± SO) tl/2 of AAA and
FAA significantly increased to 50.7 ± 21.5 and
87.8 ± 59.7 hours in patients with creatinine
clearances below 10 mllmin (0.6 Llh).
In 6 patients with chronic renal failure, the
mean (± SO) terminal tY2 of MAA was somewhat
prolonged after intravenou s administration of
dipyrone compared with that observed in 3 indi-
viduals with normal renal function (3.8 ± 2.1 vs
2.6 ± 0.7 hours); total body clearance was lower
[91.5 ± 41.7 vs 140.2 ± 37.5 mllmin/1.73m 2
(5.5 ± 2.5 vs 8.4 ± 2.25 LIhI1.73m 2)] and renal clear-
ance of AA, FAA and AAA was decreased. [301 A
possible reason for the differences observed in
the total clearance of MAA in both studies may
be that parent drug (dipyrone) is eliminated via
the kidney, after its intravenous administration,
and that this mechanism of elimination is also
impaired in patients with renal disease.
The kinetics of the metabolites of dipyrone were
also studied in 46 intensive care patients with and
without acute renal failurePl1 In patients with
acute renal impairment, a marked reduction in the
total clearance and prolongation of the plasma
Clin. Pharmacokinet. 28 (3) 1995
Pharmacokinetics of Dipyrone 229

100
o Patients with liver cirrhosis
• Healthy individuals
::J
0,
g
c
o 10
~
C
Ql
u
c
o
U
ell
E
'"
ell
Ci.
~
:2

0.1~--------'--------.--------.---------r--------'--------.--------.
o 10 20 30 40 50 60 70
Time (h)

Fig. 5. Mean 4-methyl-amino-antipyrine (MAA) plasma concentration-time curves in 12 patients with cirrhosis of the liver and 12
healthy individuals (M. Levy, E. Zylber-Katz, personal communication).

11/2 of MAA were noted. This is most likely to be
due to reduced hepatic metabolic activity.
MAA is rapidly eliminated by haemodialysis,
haemofiltration or haemoperfusion, in vitro, with
t';2 values of 6, 11 and 3 minutes, respectively,132J
3. Drug Interactions
In healthy volunteers coadministration of
20ml of aluminium hydroxide/magnesium hy-
droxide gel (Maaloxan®) did not affect the phar-
macokinetics of metabolites of dipyrone (W. Scholz,
B. Rosenkranz, personal communication).
The pharmacokinetics of alcohol (ethanol) and
the results of performance tests were similar
whether alcohol (1 g/kg) was given with dipyrone
(lg) or with placebo (L.M. Badian, B. Rosenkranz,
personal communication).
In a single-blind trial, 6 patients with non-insulin-
dependent diabetes treated with glibenclamide (gly-
buride) were given dipyrone Ig for 2 days and pla-
cebo for 5 days. In 6 other patients the order of
administration was reversed. As evident from blood
glucose profiles there was no interaction between
the 2 drugs,l33]
It has been suggested that the anticoagulant ef-
fect of ethyl-biscoumacetate is increased by di-
pyrone,134J However, a latter study has shown that
the anticoagulant activity of phenprocoumon or of
ethyl-biscoumacetate is not influenced by simulta-
neous administration of therapeutic doses of di-
pyrone. [35] When dipyrone 1g 3 times daily for 3 days
was given to healthy individuals, it did not affect
the diuretic effect offurosemide (frusemide) 20mg
administered intravenously on the third day,D6]
Little is known about whether other drugs can
inhibit or induce the metabolism of dipyrone. Fol-
lowing intravenous administration of dipyrone 1 to
1.5g to patients hospitalised in intensive care units,
no significant difference in t';2 and CLIF of MAA
was found between a group who had concomi-
tantly received a mean daily dose of 30 mg/kg
pentobarbital (pentobarbitone) and a group who
had not.[3?] The sedative glutethimide was reported
to reduce the potency of dipyrone,138]
4. Dosage and Tolerability
Dipyrone is available for oral administration in
the form of 0.5g tablets, 5% syrup and 50% aque-
ous solution as drops. A 50% aqueous solution is

© Adis International Limited. All rights reserved. Clin. Pharmacokinet 28 (3) 1995
230 Levy et al.

500 2500
MAA AA
CUF =0.37 x CL CR +147 • CUF = 2.90 x CLCR + 413
400 • 2000

•
C 300 :s.§ 1500
~
.s
u. •.•........
•• • I
u.
::::J
() 200
• • •
a 1000 • • • •
• .... . .•. .
"........
~
. .... • .. .....
100
•• •• •
•
• • 500

.-
~ ... ..-- ...... . .
0
0 24 48 72 96 120 144 168 o 24 48 72 96 120 144 168

400 600
AAA
CUF = 1.93 x CL CR + 31
... FAA
CUF = 2.61 x CL CR - 8 •
350

300 .. 500

400
C 250 c
~ :§
.s 200 • I 300
u. u.
::::J ::::J
() 150 ()
200
100
100
50

o 24 48 72 96 120 144 168 o 24 48 72 96 120 144 168

CL CR (ml/min) CL CR (ml/min)

70
o MAA: CL R = 0.02 X CLCR + 0.72
60 • AA: CL R = 0.17 X CLCR + 0.49
o AAA: CLR = 0.28 X CL CR - 0.59
50 A FAA: CL R = 0.42 X CLCR - 2.46
C ~.¥ o
:§ 40 .... ·.. ··0
AO
E . ......
~30
....J •.. .. '

.. , .. ' .. '
() '
20
•
10

0
0 24 48 72 96 120 144 168
CLCR (ml/min)

Fig. 6. Correlation between creatinine clearance (CLCR) and apparent oral clearance (CUF) or renal clearance (CLR) of 4-methyl-amino-anti-
pyrine (MAA), 4-amino-antipyrine (AA), 4-acetyl-amino-antipyrine (AAA) and 4-formyl-amino-antipyrine (FAA) in 24 patients with CLCR values
between 4 and 157 ml/min (0.24 and 9.42 Uh).[25]

© Adis International Limited . All rights reserved. Clin. Pharmacokinet. 28 (3) ] 995
Pharmacokinetics of Dipyrone
used for parenteral administration, while 1.0 and
0.3g suppositories are available for rectal adminis-
tration. The recommended dose in adults and ado-
lescents aged IS years or over is O.S to 1.0g (orally)
or 1 to 2g (parenterally) given as a slow intra-
venous injection (administered at a rate of SOOmg
per minute or less). The dose should be modified
according to the analgesic or antipyretic response.
The currently recommended maximum daily dose
is 4 to Sg, although higher doses also have been
shown to be well toleratedJ39] Dipyrone is not
recommended for infants under 3 months of age or
those under Skg bodyweightJ40]
Although the relationship between plasma con-
centrations of dipyrone metabolites and toxicity
has not been established, the therapeutic index of
dipyrone is very high. The dose that is lethal to
SO% (LD 50) of animals (rats mice, rabbits) is about
1000 mg/kg or more and subchronic toxicity in
dogs and rats, manifested by an increase in Heinz
bodies and reticulocytosis in both species and by a
reduction in haematocrit in dogs, was reported af-
ter administration of a 4S0 mg/kg doseJ40] Since
the metabolic profile of dipyrone is similar in rats
and humans, these toxicological data may be clin-
ically relevant.
There are hardly any reports in the literature of
dipyrone overdosage in humans,[41] although occa-
sionally reversible renal insufficiency has been re-
ported after an overdose of dipyroneJ42] A patient
who swallowed 98 dipyrone tablets (49g) had
symptoms of vomiting, and the urine eventually
became red. Stomach emptying and forced diuresis
were employed, and the patient recovered without
any sequelaeJ43] The red colour of the urine re-
sulted from the excretion of a putative metabolite,
rubazonic acid.[44] Agranulocytosis and the more
frequently observed skin rashes are hypersensi-
tivity reactions.[1,45]
Two cases of agranulocytosis following pro-
longed high-dose usage of intravenous dipyrone
have recently been reported. [46] However, these pa-
tients concomitantly received other drugs known
to cause agranulocytosis. Shock, as evidenced by
a critical reduction in blood pressure, may be part
© Adls International Limited. All rights reserved.
231
of an anaphylactic reaction, but can also occur as
a result of pharmacologically induced vasodila-
tion. In patients with very high fever, such as some
of those in intensive care units, or after rapid injec-
tions of dipyrone, such reductions in blood pres-
sure, without further signs of hypersensitivity, may
occurJ47]
5. Clinical Implications
and Conclusions
Dipyrone is usually used episodically for treat-
ment of acute pain and fever, although prolonged
use for musculoskeletal pain or the control of pain
in patients with cancer is also practised. The phar-
macokinetic profiles of MAA and AA are in line
with the clinically required rapid onset of effect
and compatible with a 4-times daily dosage regi-
men. The virtually complete bioavailability of
dipyrone renders the oral route of administration
favourable in most cases, except for situations
when this is not feasible or when a more rapid onset
of effect is desired, as in colic pain. The bioavail-
ability of dipyrone suppositories can be as low as
40%, making this mode of administration less fa-
vourable. Intramuscular injection has no pharma-
cokinetic advantages over the oral route.
Dipyrone, unlike most of the nonsteroidal anti-
inflammatory drugs, is not known to produce clin-
ically important interactions related to displace-
ment of other substances from plasma proteins.
This is readily explained by the relatively low pro-
tein binding of the metabolites of dipyronePOl
No significant amounts of dipyrone metabolites
will be found in the breast milk if nursing is initi-
ated more than 48 hours after the last dose of
dipyrone. [21]
At present the available information on the re-
lationship between pharmacokinetics of dipyrone
and its effect indicates that the analgesic effect of
dipyrone is correlated with both MAA and AA con-
centrations.[7] MAA has been shown to cause a
moderate inhibition of platelet aggregation and
thromboxane release from human platelets[48-50]
and prostaglandin (PG) E2 release from human
gastric mucosa.[51] Animal studies have demon-
Clin. Pharmocokinet. 28 (3) 1995
232
strated release of PGlz from rat aorta[49] and PGE2
from rabbit brain[52] in MAA concentrations sim-
ilar to those observed clinically (between about 5
and 35 )lmollL). However, other studies failed to
show an inhibition of prostanoid release by MAA
in this concentration range. AAA and FAA have
been reported to be ineffective in vitro and in iso-
lated organs, whereas it remains unclear whether
AA contributes to the inhibition of eicosanoid for-
mation after dipyrone intake.[49.53] It is also un-
known to what extent other effects of dipyrone on
the central nervous system account for its analgesic
and antipyretic action.l 54]
The pharmacological and pharmacokinetic prop-
erties of the many other metabolites of dipyrone
described recently[3] remain unclear as well as the
putative question whether one of these metabolites
contributes to the risk of adverse reactions.
Several factors explaining pharmacokinetic
variability of dipyrone have been detected. These
include saturable metabolism, N-acetylation poly-
morphism, age, possibly gender, and liver and renal
disease. Since saturable metabolism mainly affects
formation and elimination of secondary metabo-
lites, its clinical relevance remains questionable.
No dosage adjustment is required for slow and
rapid acetylators. However, the impact of pharmaco-
genetic polymorphism on the risk of adverse re-
actions is unknown. Slow acetylators of drugs such
as hydralazine, isoniazid and procainamide are not
only more susceptible to dose-related toxicity, but
also to autoimmune phenomena such as the induc-
tion of antinuclear antibodies and the lupus syn-
drome.l 55 .56 ] The question of whether the risk of
dipyrone-induced agranulocytosis is influenced by
genetic polymorphisms is intriguing, but difficult
to answer due to the rarity of the disease.
Further study of the pharmacogenetics of di-
pyrone, such as the determination of the cyto-
chrome P450 systems[57] involved with the forma-
tion of AA and FAA is of interest and could provide
clues for potential clinically important interac-
tions.
Although the data show some age and gender
differences in the pharmacokinetics of dipyrone, in
© Adis International Limited. All rights reserved.
Levy et al.
practice it is judged that overall adjustment of the
dose is not warranted. Available reports on di-
pyrone pharmacokinetics in pregnancy are defi-
cient in their analytical methodologies, and pro-
vide contradictory results, but overall these studies
do not seem to warrant changes in dosage regi-
mens. Although the elimination of dipyrone meta-
bolites is usually prolonged in liver disease, in
practice no dose adjustment seems to be necessary
when patients are being administered single doses.
For long term treatment, an increase in dosage
intervals might be advocated; this deserves further
study.
The prolonged action of the drug, combined
with its tolerability relative to nonsteroidal anti-
inflammatory drugs in patients with bleeding dis-
orders, might be advantageous in patients with cir-
rhosis who require analgesic and/or antipyretic
therapy. Furthermore, dipyrone per se is not known
to cause hepatic damage.
In patients with chronic renal disease, disposi-
tion of MAA is not markedly altered. It is question-
able whether the impaired elimination of AAA and
FAA should be accounted for in the dosage regi-
men. There have been occasional reports of tran-
sient renal disorders with oliguria or anuria, pro-
teinuria and interstitial nephritis,[42,58-60] which
may be explained by inhibition of prostanoid for-
mation or immunological mechanisms.
A multicenter case-control study, in which reg-
ular analgesic intake was defined as consumption
of at least 15 doses of analgesic per month for at
least a year, was undertaken in patients with end-
stage renal failure and controls to assess the risk of
nephropathy associated with prolonged analgesic
use. A dose-dependent increase in the risk associ-
ated with analgesic mixtures containing phenace-
tin, paracetamol (acetaminophen), aspirin (acetyl-
salicylic acid) and phenazones was noted. No
increase could be demonstrated for dipyrone-con-
taining mixtures.[61]
Population pharmacokinetics may help deter-
mine the effect of gender, and liver and kidney dis-
ease on the pharmacokinetics of dipyrone after re-
peated administration of the drug. [62] Furthermore,
Clin. Pharmacokinet. 28 (3) 1995
Pharmacokinetics of Dipyrone
this approach may highlight the presence of, as yet,
unidentified drug interactions.
The high therapeutic index of dipyrone and its
recognisable pharmacodynamic effects support the
current dosage recommendations, despite the com-
plex pharmacokinetic issues discussed above.
Acknowledgements
We would like to acknowledge the valuable contributions
of Dr Y. Caraco and Mrs L. Granit, Dr D. Schmidt, Dr M.
Volz and Dr H.G. Eckert (bioanalysis), and Dr D. Brock-
meier and Prof. H. Luus (biometrical evaluation).
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