caa a22 4500 47705711X CHVBK 20180405111349.0 cr unu---uuuuu 170330e19960501xx s 000 0 eng 10.1007/s002280050094 doi (NATIONALLICENCE)springer-10.1007/s002280050094 In vitro comparative inhibition profiles of major human drug metabolising cytochrome P450 isozymes (CYP2C9, CYP2D6 and CYP3A4) by HMG-CoA reductase inhibitors [Elektronische Daten] [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−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. hypoglyceamic sulphonylureas and oral anticoagulants) may be expected. Springer-Verlag Berlin Heidelberg, 1996 Key words HMG-CoA reductase inhibitors nationallicence drug interactions nationallicence human liver microsomes nationallicence CYP2C9 inhibition nationallicence CYP2D6 inhibition nationallicence CYP3A4 inhibition nationallicence Transon C. Division of Clinical Pharmacology, University Hospitals, 24, rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland, CH aut Leemann T. Division of Clinical Pharmacology, University Hospitals, 24, rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland, CH aut Dayer P. Division of Clinical Pharmacology, University Hospitals, 24, rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland, CH aut https://doi.org/10.1007/s002280050094 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s002280050094 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Transon C. Division of Clinical Pharmacology, University Hospitals, 24, rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland, CH aut NATIONALLICENCE 700 1- Leemann T. Division of Clinical Pharmacology, University Hospitals, 24, rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland, CH aut NATIONALLICENCE 700 1- Dayer P. Division of Clinical Pharmacology, University Hospitals, 24, rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland, CH aut Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer