Comparison of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) as inhibitors of cytochrome P450 2C8.
Statins are involved in different types of drug interactions. Our objective was to study the effect of statins on cytochrome P450 (CYP) 2C8-mediated paclitaxel 6 alpha-hydroxylation by incubating paclitaxel and statins (0--100 microM) with pooled human liver microsomes. Simvastatin, lovastatin, atorvastatin and fluvastatin were the most potent inhibitors of CYP2C8 activity with K(i) (IC(50)) values of 7.1 (9.6) muM, 8.4 (15) microM, 16 (38) microM and 19 (37) microM, respectively. Cerivastatin, simvastatin acid and lovastatin acid were less potent inhibitors with K(i) (IC(50)) values ranging from 32 to 55 (30--67) microM. Rosuvastatin and pravastatin showed no appreciable effect on CYP2C8 activity even at 100 microM. In conclusion, all the statins tested, except rosuvastatin and pravastatin, had a significant inhibitory effect on the activity of CYP2C8 in vitro. Because many of the statins accumulate in the liver and because also their metabolites may inhibit CYP2C8 activity, in vivo studies are needed to investigate a possible interaction of simvastatin, lovastatin, atorvastatin and fluvastatin with CYP2C8 substrate drugs.
Tornio
Aleksi
A
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
Pasanen
Marja K
MK
Laitila
Jouko
J
Neuvonen
Pertti J
PJ
Backman
Janne T
JT
D000465:Algorithms; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D065727:Cytochrome P-450 CYP2C8; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D006900:Hydroxylation; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D017239:Paclitaxel / Q000378:metabolism; D043823:Taxoids / Q000493:pharmacokinetics
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D043823:Taxoids; C086219:6-hydroxytaxol; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D017239:Paclitaxel