Sex difference in antipyrine 3-hydroxylation: An in vivo-in vitro correlation of antipyrine metabolism in two rat strains

doi:10.1016/0006-2952(90)90314-B

Biochemical Pharmacology

Volume 40, Issue 4, 15 August 1990, Pages 771-777

https://doi.org/10.1016/0006-2952(90)90314-B Get rights and content

Abstract

Antipyrine metabolism depends on at least three isoenzymes of cytochrome P450 forming the main metabolites 3-OH-, 4-OH- and norantipyrine. We investigated to which extent antipyrine clearance and metabolite formation in vivo correlate with metabolite formation by microsomal fractions in vitro. The influence of sex was investigated in two rat strains. Antipyrine clearance in saliva was determined in 10-month-old Sprague-Dawley and Dark Agouti rats of either sex. Antipyrine and its metabolites in urine and microsomes were measured by a new HPLC method after solid phase or liquid extraction. Antipyrine clearance was 46% higher in males than in female rats. This was associated with a 40% higher urinary excretion of 3-OH-antipyrine in the male rats, the other metabolites being excreted to a similar extent. This higher production of 3-OH-antipyrine in vivo was paralleled by a higher intrinsic clearance in vitro while no sex difference in intrinsic clearance for the formation of the other metabolites was seen. The correlation between in vivo and in vitro metabolic clearance for 3-OH-antipyrine was good (r = 0.75) but unconvincing for 4-OH- (r = 0.49) and norantipyrine (r = 0.01). This could be due to further metabolism of 4-OH- and norantipyrine.

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Antipyrine metabolism depends on at least three isoenzymes of cytochrome P450 forming the main metabolites 3-OH-, 4-OH- and norantipyrine. We investigated to what extent antipyrine clearance and metabolite formation are impaired in two models of liver cirrhosis in the rat, namely micronodular cirrhosis induced by chronic exposure to phenobarbital/CCl₄ and biliary cirrhosis induced by bile duct ligation. Salivary antipyrine clearance was decreased to a similar extent in cirrhosis induced by CCl₄ and bile duct ligation (−35%). Clearance for production of 3-OH-antipyrine was decreased in both models, while 4-hydroxylation was maintained. Metabolic clearance of both 3-OH-antipyrine and 4-OH-antipyrine in vivo correlated with their clearance in vitro (r = 0.658 and r = 0.583) but not with that of norantipyrine. The microsomal cholesterol content was increased by 16% and 90% in CCl₄ and bile duct-ligated cirrhotic rats (P < 0.001), respectively. Membrane fluidity, expressed as the ratio of phospholipids to cholesterol, correlated with the in vivo clearance for production of norantipyrine (r = 0.841) but not of 3-OH- or 4-OH-antipyrine, while clearance in vitro was not related lipid composition. Our results demonstrate that the cytochrome P450 isoenzymes responsible for the different pathways of antipyrine metabolism are affected to different extents by cirrhosis. Alterations in intrinsic clearance explain only part of the loss of hepatocellular function. Altered lipid composition contributes to this loss of function but other factors, among them loss of hepatocytes and changes in microcirculation, could be more important determinants of the decrease in xenobiotic metabolism in cirrhosis.
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Sex difference in antipyrine 3-hydroxylation: An in vivo-in vitro correlation of antipyrine metabolism in two rat strains

Abstract

J Hepatol

Biochem Pharmacol

Life Sci

Biochem Pharmacol

Chem Biol Interact

J Biol Chem

J Biol Chem

J Chromatogr (Biomed Appl)

J Chromatogr (Biomed Appl)

Comput Biol Med

J Pharmcol Sci

Biochem Pharmacol

Clearance concepts in pharmacokinetics

J Pharmacokin Biopharm

The fate of antipyrine in man

J Pharmacol Exp Ther

A radiometric high-pressure liquid chromatography assay for the simultaneous determination of the three main oxidative metabolites of antipyrine. Studies in vitro

Anal Biochem

Comparison of the in vivo and in vitro rates of formation on the three main oxidative metabolites of antipyrine in man

Br J Clin Pharmacol

Monogenetic control of variations in antipyrine metabolite formation. New polymorphism of hepatic drug oxidation

J Clin Invest

Interindividual variation in antipyrine metabolism formation in healthy volunteers. Antipyrine metabolite profile as a tool in the assessment of the activity of different drug oxidizing enzymes in man

Antipyrine metabolism in relationship to polymorphic oxidation of sparteine and debrisoquine

Br J Clin Pharmacol

The influence of the genetically controlled deficiency in debrisoquine hydroxylation on antipyrine metabolite formation

Pharmacology

Biochemical basis of sex differences in drug metabolism

Pharmacol Ther