Role of human cytochrome p450 3A4 in metabolism of medroxyprogesterone acetate

Medroxyprogesterone acetate (MPA) is a drug commonly used in endocrine ther apy for advanced or recurrent breast cancer and endometrial cancer. The dru g is extensively metabolized in the intestinal mucosa and in the liver. Cyt ochrome P450s (CYPs) involved in the metabolism of MPA were identified by u sing human liver microsomes and recombinant human CYPs, In this study, the overall metabolism of MPA was determined as the disappearance of the parent drug from an incubation mixture. The disappearance of MPA in human liver m icrosomes varied 2.6-fold among the 18 samples studied. The disappearance o f MPA in the same panel of 18 human liver microsomes was significantly corr elated with triazolam cw-hydroxylase activity, a marker activity of CYP3A ( r = 0.764; P < 0.001). Ketoconazole, an inhibitor of CYP3A4, potently inhib ited the disappearance of MPA in 18 human liver microsomes, Anti-CYP3A anti body also inhibited 86% of the disappearance of MPA in human liver microsom es, Although sulfaphenazole tan inhibitor of CYP2C9) and S-mephenytoin tan inhibitor of CYP2C19) partially inhibited the disappearance of MPA, no effe ct of the anti-CYP2C antibody was observed. The disappearance of MPA did no t correlate with either the activity metabolized via CYP2C9 (diclofenac 4'- hydroxylase activity) or the activity metabolized via CYP2C19 (S-mephenytoi n 4'-hydroxylase activity). Among the 12 recombinant human CYPs (CYP1A1, CY P1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP 3A4, and CYP3A5) studied, only CYP3A4 showed metabolic activity of MPA, The se results suggest that CYP3A4 is mainly involved in the overall metabolism of MPA in human liver microsomes.