In vitro comparative inhibition profiles of major human drug metabolising cytochrome P450 isozymes (CYP2C9, CYP2D6 and CYP3A4) by HMG-CoA reductase inhibitors
In vitro comparative inhibition profiles of major human drug metabolising cytochrome P450 isozymes (CYP2C9, CYP2D6 and CYP3A4) by HMG-CoA reductase inhibitors
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DOI：
10.1007/s002280050094
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发表时间：
1996
影响因子：
2.9
通讯作者：
C. Transon;T. Leemann;P. Dayer
中科院分区：
文献类型：
--
作者：
C. Transon;T. Leemann;P. Dayer
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 Ki> 50 μmol⋅l−1). Racemic and (+)- and (−)-fluvastatin showed moderate affinity (estimated Ki> 50 μmol⋅l−1) for CYP2D6 and CYP3A4, whereas their affinity for CYP2C9 was high (estimated Ki< 1 μmol⋅l−1). Diclofenac 4′-hydroxylation was competitively and stereoselectively inhibited, with measured Ki’s of 0.06 and 0.28 μmol⋅l−1for (+)- 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 vivodrug interactions by inhibition of liver oxidation of CYP2C9 substrates (e.g. hypoglyceamic sulphonylureas and oral anticoagulants) may be expected.
