Antipyrine, metabolism

Antipyrine (l,2-dihydro-l,5-dimethyl-2-phenyl-3H-pyrazole-3-one) is anM-me-thylated analgesic drug which is primarily metabolized in the liver by microsomal cytochrome P450 enzymes [3, 61-68] (Fig. 3). The three main oxidative metabolites of antipyrine are 4-hydroxyantipyrine, 3-hydroxymethylantipyrine, and norantipyrine. 

A combination of various properties of antipyrine gives it an advantage over other microsomal enzyme metabolizing drugs. These include high oral availability useful for non-invasive oral administration, lack of plasma protein binding which prevents environmental clearance variability, and fast distribution 

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Fraser, H. S., Mucklow, J. C. et al. (1979). Environmental factors affecting antipyrine metabolism in London factory and office workers. Br. J. Clin. Pharmacol., 7(3), 237-43. 

Antipyrine metabolism in vivo has also been demonstrated. Following extraction of media from uptake and elimination studies, TLC analysis revealed the parent compound and 4-hydroxy-antipyrine. Based upon the amount of radioactivity recovered, the metabolite may account for up to 4% of the total. This hy-droxylated metabolite is the primary oxidation product in animals studied to date (23). Further characterization of the extracts using high-pressure liquid chromatography will be done in the future. 

Mucklow JC, Fraser HS. The effects of age and smoking upon antipyrine metabolism. BrJ Clin Pharmacoi 1980 9 612-614. 

Studies of antipyrine metabolism may be used to illustrate the effect of inhibition on metabolism in vivo in addition, these studies have demonstrated variation among species in the inhibition of the metabolism of xenobiotics. In the rat, a dose of piperonyl butoxide of at least 100 mg/kg was necessary to inhibit antipyrine metabolism, whereas in the mouse a single intraperitoneal (IP) or oral dose of 1 mg/kg produced a significant inhibition. In humans an oral dose of 0.71 mg/kg had no discernible effect on the metabolism of antipyrine. 

For example, on the 3 occasions where regression analysis was applied, 3 divergent conclusions were reached on the effect of sex on antipyrine metabolism. Despite different populations in each study, ethnic differences alone probably do not explain the discrepancies. Possibly too much reliance has been placed on the statistical significance of p values derived from the model based on multiple regression analyses, particularly when the correlations themselves are low and the subjects are under highly perturbed environmental conditions (35,36). Whereas the results of such studies on causes of variability in antipyrine kinetics may provide valuable clues, the conclusions and clues drawn from the model that uses multiple regression analyses should be validated by a carefully controlled, prospective experiment before safe acceptance. 

Homeida M, Halliwell M, Branch RA. Effects of an oral contraceptive on hepatic size and antipyrine metabolism in premenopausal women. Clin Pharmacol Ther 1978 24(2) 228-32. 

Abernathy DR, Greenblatt DJ. 1981. Impairment of antipyrine metabolism by low dose oral contraceptive steroids. Clin. Pharrn. Ther. 29 106-110. 

Ethnic variations in diet, additives or salt content may alter metabolism rates. Lin et al. (1986) and Henry et al. (1987) report that antipyrine metabolism was different in rural Asian Indians than in Asian Indian immigrants resident in England for some years. Dietary environmental differences may also account for the findings of Gould et al. (1972) andKato etal. (1973) of a gradation ofheart and stroke incidence, lowest in residents of rural Japan, higher in Japanese in Hawaii and highest in Japanese in California. 

To assess selectivity in the inducing and inhibiting effects of environmental factors (for example, dmg treatment) on the activity of the different P-450 enzymes. In one of such smdies, nifedipine, sparteine, mephenytoin and antipyrine were administered simultaneously to 15 healthy subjects, including four poor metabohzers of sparteine and four poor metabolizers of mephenytoin [6], They received the cocktail on three different occasions without pretreatment, after pentobarbital pretreatment and together with cimetidine. Concentrations of nifedipine, its pyridine metabolite, and of sparteine and its dehydro metabolite were measured in the plasma nifedipine metabohtes, sparteine, dehydrosparteine, 4-hydroxymephenytoin, antipyrine and its three major metabohtes were all measured in urine. The kinetic parameters obtained clearly indicated that nifedipine metabolism is very sensitive to pentobarbital induction (Fig. 4), whereas antipyrine metabolism is sensitive only to a moderate degree and sparteine metabolism is unaffected. Cimetidine inhibited the metabohc clearance of all three compounds to a similar extent and also inhibited renal clearance of sparteine, most likely at the level of tubular secretion. Urinary excretion of 4-... 

Abemethy DR, Greenblatt DJ, Steel K. Propoxyphene inhibition of doxepin and antipyrine metabolism. Clin Pharmacol fher (1982) 31,199. 

Loft, Sonne J, Poulsen HE, PetersenKT, Jorgensen BG, Dossir M Inhibitioi and induction of metronidazole and antipyrine metabolism. EurJ Clin Pharmacol 9ZT) 32,35 1. 

Inaba, T., and Fischer, N. E. Antipyrine Metabolism in Man Simultaneous Determination of Noranti-pyrine and 4-Hydroxyantipyrine in Urine by Gas Chromatography... 

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