Inhibition of antipyrine metabolite formation in rats<i>in vivo</i>

A simple model simulating the kinetics of drug metabolism inhibition interaction is investigated. The relative sensitivity of drug and metabolite concentration-time profiles as indices of inhibition is assessed. Under steady-state conditions where inhibitor concentrations are maintained constant, the determination of metabolite in addition to drug kinetics provides little additional information when inhibition is nonselective in nature. However metabolite profiles do offer increased sensitivity when parallel routes of metabolism exist and there is selectivity of inhibitory action. Non-steady-state conditions are also investigated as they often apply in inhibition studies; the inhibitor is often administered as a single dose or as a multiple dosing regimen rather than by a constant rate intravenous infusion. Under the former conditions, when inhibitor concentrations in the body fluctuate during the study, metabolite kinetics can be more useful than drug kinetics. The changes evident in the metabolite concentration-time profiles are substantial due to both the inhibition per se and the nonlinearity in the system arising from inhibitor elimination. It is concluded that metabolite kinetics provide a useful aid in the detection of drug metabolism inhibition interactions.

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Kinetics of drug metabolism inhibition: Use of metabolite concentration-time profiles

Shaw

Houston

1987

Journal of Pharmacokinetics and Biopharmaceutics

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The effect of velnacrine on the mixed function oxidase system

Eccles

Danbury

Ford

et al. 1997

European Journal of Drug Metabolism and Pharmacokinetics

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Velnacrine is a centrally acting anticholinesterase which has been considered for use in the treatment of Alzheimer's disease. If proven to be of value, it will be used concurrently with other medications. Its potential to cause interaction is, therefore, important to study. The aim of this work was to investigate velnacrine as an inhibitor of hepatic oxidative enzymes. The effects of velnacrine on antipyrine metabolism in isolated rat hepatic microsomes were compared to those of cimetidine. Aliquots of 200, 250 and 300 micrograms/ml antipyrine were incubated alone, with 20 micrograms/ml cimetidine and with each of 20, 50 and 100 micrograms/ml velnacrine. The concentrations of antipyrine and of its metabolites, 3-hydroxymethylantipyrine, 4-hydroxyantipyrine and norantipyrine were assayed by reverse phase high performance liquid chromatography. Cimetidine inhibited production of all three metabolites. Velnacrine did not affect 3-hydroxymethylantipyrine production. Mean inhibition of 4-hydroxyantipyrine production of 15%, 30% and 25% (P < 0.01), and of 14%, 25% and 12% of norantipyrine production (P < 0.01) occurred. These results indicate that velnacrine may inhibit the enzymes responsible for the metabolism of antipyrine to norantipyrine and 4-hydroxyantipyrine. The clearance rate of drugs that are metabolised through the hepatic oxidase system may, therefore, be reduced in the presence of concurrent treatment with velnacrine.

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Studies on rat liver cytochrome P-450s involved in the metabolism of antipyrine: phenobarbital- and 3-methylcholanthrene-inducible isozymes possessing 4-hydroxylase activity

Buppodom

Koga

Yamada

et al. 1986

Biochemical Pharmacology

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Inhibition of antipyrine metabolite formation in ratsin vivo

Cited by 17 publications

References 22 publications

Kinetics of drug metabolism inhibition: Use of metabolite concentration-time profiles

Kinetics of drug metabolism inhibition: Use of metabolite concentration-time profiles

The effect of velnacrine on the mixed function oxidase system

Studies on rat liver cytochrome P-450s involved in the metabolism of antipyrine: phenobarbital- and 3-methylcholanthrene-inducible isozymes possessing 4-hydroxylase activity

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