Roles of different CYP enzymes in the formation of specific fluvastatin metabolites by human liver microsomes.

Takaki Toda, Erik Eliasson, Birgitta Ask, Nobuo Inotsume, Anders Rane

Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.

Basic & clinical pharmacology & toxicology 2009 Nov

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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.

Citation

Takaki Toda, Erik Eliasson, Birgitta Ask, Nobuo Inotsume, Anders Rane. Roles of different CYP enzymes in the formation of specific fluvastatin metabolites by human liver microsomes. Basic & clinical pharmacology & toxicology. 2009 Nov;105(5):327-32