Received for publication March 13, 2008.
Revised June 18, 2008.
Accepted for publication June 19, 2008.

Identification of enzymes involved in the metabolism of 17-hydroxyprogesterone Caproate (17-OHPC): An effective agent for prevention of pre-term birth

Abstract

Preterm delivery, that is delivery before 37 completed weeks of gestation, is the major determinant of neonatal morbidity and mortality. Until recently no effective therapies for prevention of preterm birth existed. In a recent multicentered trial, 17- hydroxyprogesterone caproate (17-OHPC) reduced the rate of preterm birth by 33% in a group of high risk women. Limited pharmacologic data exist for this drug. The recommended dose is empiric, the metabolic pathways are not well defined especially in pregnant women and the fetal exposure has not been quantified. In order to define the metabolic pathways of 17-OHPC we used human liver microsomes, fresh human hepatocytes and expressed enzymes. Human liver microsomes (HLM) in the presence of NADPH generated 3 major metabolites (M1, M2, and M3); whereas 2 major metabolites (M1, M2) were observed with fresh human hepatocytes (FHH). Metabolism of 17-OHPC was significantly inhibited by the CYP3A4 inhibitors ketoconazole and troleandomycin in HLM and FHH. Metabolism of 17-OHPC was significantly greater in FHH treated with the CYP3A inducers, rifampin and phenobarbital. Further, studies with expressed enzymes demonstrated that 17-OHPC is metabolized exclusively by CYP3A4 and CYP3A5. The caproic acid ester was intact in the major metabolites generated indicating that 17-OHPC is not converted to the primary progesterone metabolite, 17- hydroxyprogesterone (HP). In summary, this study demonstrates that 17-OHPC is metabolized by CYP3A. Since, CYP3A is involved in the oxidative metabolism of numerous commonly used drugs; 17-OHPC may be involved in clinically relevant metabolic drug interactions with co-administered CYP3A4 inhibitors or inducers.

Key words: CYP3A, cytochrome P450