Eur J Clin Pharmacol (1990) 38:61~5

he ecel]e® © Springer-Verlag1990

Pharmacokinetics of metamizol metabolites in healthy subjects after a single oral dose of metamizol sodium V. V l a h o v 1, M. B a d i a n 2, M. V e r h o 2, and N. B a c r a c h e v a 1 Chair of Clinical Pharmacology, Institute of Pharmacology and Pharmacy, Medical Academy, Sofia, Bulgaria and 2 Hoechst-AG, Frankfurt/Main, West Germany

Summary. The linearity of the pharmacokinetics of the metamizol metabolites 4-methyl-amino-antipyrine (4M A A ) , 4-amino-antipyrine (4-AA), 4-formyl-aminoantipyrine (4-FAA), and 4-acetyl-amino-antipyrine (4A c A A ) has b e e n studied after adminstration to 15 healthy male volunteers of single oral doses of 750, 1500, and 3000 mg metamizol. The trial was open, randomized, and cross-over, with a one-week interval between dosing days. Metabolite concentrations in serum and urine were measured using reverse-phase H P L C . The m e a n Cmaxof 4 - M A A increased linearly with dose whereas its A U C was not proportional to dose after administration of 1500 and 3000 mg. With 4-AA, the increase in m e a n Cmaxwas linear, but the increase in A U C was not. The increases in m e a n Cm,x and A U C for 4-FAA after doses of 1500 and 3000 mg were not proportional to the dose. The increases in m e a n Cm~x and A U C for 4 - A c A A were roughly proportional to the increase in dose. There were no significant differences in renal clearance between doses for any of the four metabolites. The observed non-linearities reflect the saturability of metabolic pathways. However, although they were statistically significant, the deviations from linearity were marginal and should not be of clinical relevance to the analgesic efficacy of metamizol in the dose range tested. Key words: metamizol; metabolite pharmacokinetics,

that the analgesic effect of metamizol is correlated with the time-course of the 4 - M A A concentration in serum (Rohdenwald et al., unpublished data on file at Hoechst). 4 - M A A is further metabolized to 4-formyl-amino-antipyrine (4-FAA) and 4-amino-antipyrine (4-AA), the latter being acetylated to 4-acetyl-amino-antipyrine (4A c A A ) ; [4, 5, 6]. The metabolism of metamizol is shown in Fig. 1. The aim of the present study was to investigate the pharmacokinetics of metamizol metabolites after single oral doses of metamizol sodium 750, 1500, and 3000 rag.

Subjects and methods

Subjects Fifteen healthy male volunteers aged 22 to 31 y (mean 23.1, SEM 2.4 y) and weighing 76.6 (8.6) kg (range 67 to 98 kg) took part after giving their written informed consent. They were non-smokers and had to abstain from alcoholic beverages or any medication from 48 h before until 72 h after the last dose. On the first study one of the subjects refused further participation in the study and was replaced. Medical history, physical examination, and laboratory tests, including complete blood count, urinalysis, and biochemical profile, were recorded before and 24 h after completion of the study. The findings for all subjects were within the references range.

dose-linearity, healthy volunteers

Study Design

Metamizol sodium (noramidopyrine, dipyrone) is a widely used analgesic with antipyretic and anti-inflammatory properties. It is rapidly and almost completely absorbed from the gastrointestinal tract [1, 2]. The parent drug can be detected in serum for only a short time after intravenous administration, being converted to at least seven metabolites, of which four can be identified. After oral administration the absorption of metamizol is preceded by hydrolysis to 4-methyl-amino-antipyrine (4-MAA) in gastric juce [3]. It has recently been shown

The study was carried out according to the recommendations for clinical trials in man (Declaration of Helsinki, Venice Revision, 1983). The study protocol was approved by the Board of the Medical Academy in Sofia. The study was randomized, open and cross-over. The wash-out period between treatments was i week. After an overnight fast 750, 1500 or 3000 mg of metamizol (1.5, 3, or 6 film-coated tablets of Novalgin®, Hoechst AG, FRG) were given as a single oral dose with 125 ml tap water. A standardized breakfast, lunch and dinner were served 2, 5, and 10 h after administration. Hourly for 12 h after administration the subjects took 125 ml mineral water. Blood samples (5 ml) were collected in non-heparinized tubes before and 0.25, 0.5, 0.75,1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10,12, 24,

V. Vlahov et al.: Kinetics of metamizol metabolites

62

read at ~, = 265 nm (Jasco 100-III UV-photometer, USA). Isopropylantipyrine (20 gl; 25 gg.m1-1 in water) was used as the internal standard. The method has sensitivity [imits of 0.1 and 2 gg. ml -~ for serum and urine, respectively. The precision of the assay for the separate metabolites was between 2.0 and 9.5% in serum, and between 2.3 and 5.1% in urine. The accuracy ranged from - 14.9 to - 38.5% in serum and from - 20.75 to 3.95% in urine. The linearity of the method in serum and urine, was confirmed for the measured range of all the metabolites. Interfering peaks were not detected in serum or urine samples.

Metomizot

Vq NO@

3S-CH 2 -N-

0 " ~ N N_ CH3

© { 351.~ }

Hydrotysis /,- Ntethyt- omi no-o nt ipyriae CH3 - HN - R (2173)

Demethy[otion /

Pharmacokinetic Evaluation and Statistical Analysis

~

4- Amino- ontipyrine

Oxidation

A sum of exponential functions was adjusted to the individual time courses of 4-MAA concentrations in the serum:

L- Formyl- amino-antipyrine

H2N- R

HC-HN- R

C)

(203.3)

L Acetytotion

C = ~ Cie-x' (t 'lag) i=i

(231.3)

/-- At.etyl, - ornino- ant ipyrine CH3CO-HN- R (245.3)

Fig. 1. The metabolism of metamizol to 4-methyl-amino-antipyrine (4-MAA), 4-formyl-amino-antipyrine (4-FAA), 4-amino-antipyrine (4-AA), and 4-acetylamino-antipyrine (4-AcAA), modified according to Levy et al. (1984) (molecular weights are shown in parentheses)

C

,,9/mr I

100.0

10.0

1.0

where G is the intercept of the exponential function, )q is the rate constant, and tlag is the lag-time. The sum of all C~ equals zero. The fall in individual concentrations had either a mono- or bi-exponential course. For the other metabolites (4-AA, 4-FAA, 4-AcAA), a single exponential was adjusted to the terminal log-linear segment of the concentration-time curves, using a non-linear Gauss-Newton procedure, modified according to Stoer [8], and with Schmidt's algorithm for orthogonalization [9]. Maximum concentrations (Cm~x) and the times to reach maximum concentrations (tmax) w e r e read from the original data. In the case of 4-MAA the adjusted function (t) was used to compute the area under the curve (AUC), the relative total clearance (CL/f), the relative total apparent volume of distribution (V~/f), the mean residence time (MRT), and the terminal half-life (tl/2) [10, 11, 12]. For the other metabolites the area under the curve (AUCm_~0) was computed by means of the linear trapezoidal method and completed by extrapolation (AUC(t_~=)= C(t)/)~); the sum of AUCm_~1 and AUC

Pharmacokinetics of metamizol metabolites in healthy subjects after a single oral dose of metamizol sodium.

The linearity of the pharmacokinetics of the metamizol metabolites 4-methyl-amino-antipyrine (4-MAA), 4-amino-antipyrine (4-AA), 4-formyl-aminoantipyr...
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