Roles of different CYP enzymes in the formation of specific fluvastatin metabolites by human liver microsomes.
Fluvastatin has been considered to be metabolised to 5-hydroxy fluvastatin (M-2), 6-hydroxy fluvastatin (M-3) and N-desisopropyl fluvastatin (M-5) in human liver microsomes by primarily CYP2C9. To elucidate the contribution of different CYP enzymes on fluvastatin metabolism, we examined the effect of CYP inhibitors and CYP2C-specific monoclonal antibodies on the formation of fluvastatin metabolites in human liver microsomes. Human liver microsomes were incubated with fluvastatin with or without pre-treatment with CYP inhibitors or monoclonal antibodies. Selective inhibitors of CYP2C9 (sulfaphenazole), CYP3A (ketoconazole) and CYP2C8 (quercetin) were employed and monoclonal antibodies were against CYP2C8, CYP2C9, CYP2C19 and CYP2C8/9/18/19. According to the amount of fluvastatin metabolites produced, the formation of M-3 was found to be major pathway of fluvastatin metabolism (the relative contribution was calculated to be more than 80%). Sulfaphenazole inhibited the formation of M-2 largely, but had little effect on the formation of M-3. It also inhibited the formation of M-5. Ketoconazole markedly inhibited the formation of M-3, but did not inhibit the formation of M-2 and M-5. Quercetin had a moderate inhibitory effect on the formation of all three fluvastatin metabolites. Monoclonal antibodies against CYP2C9 and CYP2C8/9/18/19 markedly inhibited the formation of M-2 and M-5. None of monoclonal antibodies showed clear inhibition on the formation of M-3. In contrast to previous published work, our results suggest that M-2 and M-5 are formed preferentially by CYP2C9, and that M-3 is mainly formed by CYP3A. In summary, the results contribute to a better understanding of the drug-drug interaction potential for fluvastatin in vivo.
Toda
Takaki
T
Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
Eliasson
Erik
E
Ask
Birgitta
B
Inotsume
Nobuo
N
Rane
Anders
A
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004347:Drug Interactions; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism* / Q000494:pharmacology; D000077340:Fluvastatin; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000378:metabolism* / Q000494:pharmacology; D007654:Ketoconazole / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism*; D011794:Quercetin / Q000494:pharmacology; D013426:Sulfaphenazole / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; C400322:cytochrome P-450 CYP2C subfamily; D013426:Sulfaphenazole; D000077340:Fluvastatin; D003577:Cytochrome P-450 Enzyme System; D011794:Quercetin; D051544:Cytochrome P-450 CYP3A; D007654:Ketoconazole