In vitro comparative inhibition profiles of major human drug metabolising cytochrome p450 isozymes (CYP2C9, CYP2D6 and CYP3A4) by HMG-CoA reductase inhibitors

Objective: The affinity of (+)-, (-)- and (+/-)-fluvastatin, a new synthetic HMG-CoA reductase inhibitor developed as a racemate, for specific human P450 monooxygenases in liver microsomes was compared with that of the pharmacologically active acidic forms of lovastatin, pravastatin and simvastatin. Methods: Affinity was determined as the inhibitory potency for prototype reactions for 3 major drug metabolising enzymes: diclofenac 4'-hydroxylation (CYP2C9), dextromethorphan O-demethylation (CYP2D6), and midazolam 1'-hydroxylation (CYP3A4). Results: Lovastatin acid, pravastatin and simvastatin acid displayed moderate affinity for all three P450 isozymes (estimated K-i > 50 mu mol . l(-1)). Racemic and (+)- and (-)-fluvastatin showed moderate affinity (estimated K-i > 50 mu mol . l(-1)) for CYP2D6 and CYP3A4, whereas their affinity for CYP2C9 was high (estimated K-i < 1 mu mol . l(-1)). Diclofenac 4'-hydroxylation was competitively and stereoselectively inhibited, with measured K-i's of 0.06 and 0.28 mu mol . l(-1) for (+)- and (-)-fluvastatin, respectively. Conclusion: Fluvastatin selectively inhibits a major drug metabolising enzyme (CYP2C9), the (+)-isomer (pharmacologically more active) showing 4-5 fold higher affinity. As already reported for lovastatin and simvastatin, in vivo drug interactions by inhibition of liver oxidation of CYP2C9 substrates (e.g. hypo-glyceamic sulphonylureas and oral anticoagulants) may be expected.