CYP3A ISOFORMS MEDIATED ENANTIOSELECTIVE DRUG METABOLISM WITH HUMAN LIVER MICROSOMES

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Cytochrome P450 (CYP) enzymes are involved in various types of oxidation metabolism of therapcutically useful drugs. CYP3A isoforms are the most abundantly expressed P450 enzymes in human liver. Because therapeutic drugs are often used as a racemic mixture containing enantiomers having distinct pharmacokinetic and pharmacodynamic propertics, an enantioselective hepatic drug metabolism results in an enantiomeric ratio that significantly differs from unity thus introducing diffculties in interpreting plasma racemic drug concentration with regard to its pharmacodynamic effects. In order to investigate the role of CYP3A isoforms in an enantiosclcctive hepatic metabolism of a therapeutically important antiarrhythmic drug. disopyramide, we studied the in vitro metabolism of CYP3A-mediated mono-N-deallylation of the enantiomers of the drug and found that the in vitro enzyme kinetic parameters regarding enantioselective differences in the intrinsic hepatic clearance obtained from Vmax/Km valuce would show a good agreement with the in vivo enantiosclectiive pharmacokineties of the drug. Based upon these data, we concluded that in vivo enantioselective pharmacokinctics of drugs of which metabolism is mediated by CYP3A may be extrapolated from the in vitro enzyme kinetics obtained with human liver microsomes.