[In vitro tests of hepatic oxidation in man, predictive of drug interactions]

Abstract

Liver monooxygenases are of primary importance in the metabolism of numerous drugs. Their activity, which is genetically controlled, is modulated by environmental factors such as drug treatment. We have developed an in vitro model of human oxidative metabolism in order to evaluate the activity of a specific monooxygenase (debrisoquine type of cytochrome P-450). Substances capable of inhibiting monooxygenase function can be identified and the in vivo occurrence of drug interactions can thus be predicted. - Dextromethorphan O-demethylation in human microsomes prepared from small human liver tissue samples is monitored as the prototype reaction. The kinetic parameters of this reaction are stable and reproducible (Km 1-5 microM, Vmax 9.1 +/- SD 4.6 nmol x mg P-1 x h-1). The reaction is inhibited by numerous drugs (quinidine, phenothiazine type neuroleptics, some dihydropyridines). Preliminary clinical results demonstrate the predictive value of this assay.