Purpose: The objectives were to determine the cytochrome P450 (CYP) enzymes involved in the metabolism of ospemifene and its main hydroxylated metabolites and to examine the effects of CYP inhibitors and inducers on ospemifene pharmacokinetics.
Methods: In vitro metabolism studies were conducted using human liver microsomes; CYP-selective inhibitors and CYP-specific substrates were used to determine the roles of nine CYP isoforms in ospemifene metabolism. Two Phase 1 clinical trials were conducted in healthy postmenopausal women; crossover designs examined the effects of pretreatment with the CYP modulators rifampicin, ketoconazole, fluconazole and omeprazole on ospemifene pharmacokinetics.
Results: Although several CYP inhibitors decreased the in vitro formation of ospemifene metabolites, none of them completely blocked metabolism. Roles for CYP3A4, CYP2C9, CYP2C19 and CYP2B6 in the metabolism of ospemifene and its two main metabolites, 4--hydroxyospemifene and 4'-hydroxyospemifene, were confirmed. The in vivo experiments demonstrated that ospemifene serum concentrations were decreased by rifampicin pretreatment, increased by ketoconazole or fluconazole pretreatment, and minimally affected by omeprazole pretreatment.
Conclusions: The clinical pharmacokinetic findings and in vitro data suggest that CYP3A4 is important for ospemifene metabolism, but other CYP isoforms and metabolic pathways also contribute. Strong CYP3A or CYP2C9 inducers (e.g. rifampicin) would be expected to decrease the exposure to ospemifene. Ospemifene should be used with caution when coadministered with the modest CYP3A inhibitor ketoconazole and should not be coadministered with the potent CYP3A/CYP2C9/CYP2C19 inhibitor fluconazole. The potent CYP2C19 inhibitor omeprazole is unlikely to cause clinically significant changes in ospemifene pharmacokinetics.
Keywords: fluconazole; ketoconazole; omeprazole; rifampicin; selective estrogen receptor modulator.
Copyright © 2013 John Wiley & Sons, Ltd.