Short Communication Metabolism of 17-Hydroxyprogesterone Caproate, an Agent for Preventing Preterm Birth, by Fetal Hepatocytes

Pretermdelivery (i.e., deliverybefore37completedweeksofgestation) is a 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) was shown to reduce the rate of preterm birth by 33 % in a group of high-risk women. Limited pharmacologic data exist for this drug. Previous studies have shown that CYP3A is involved in the me-tabolism of 17-OHPC. In this study, we evaluated the metabolism of 17-OHPC in adult and fetal human hepatocytes and in expressed cytochrome P450 enzymes. 17-OHPC was metabolized by ex-pressed CYP3A7 and by fetal hepatocytes. The metabolite profile was qualitatively different between expressed CYP3A4 and CYP3A7. Expressed CYP3A4 demonstrated a significantly higher (>10 times) capacity to metabolize 17-OHPC than CYP3A7. Based on retention times, two unique metabolites were observed in the fetal and adult hepatocyte systems along with one common me-tabolite. The intrinsic clearance of 17-OHPC by fetal hepatocytes was observed to be one-half of that in adults. In summary, this study demonstrates that fetal hepatocytes and, in particular, the fetal form of CYP3A (i.e., CYP3A7) can metabolize 17-OHPC. Fetal drug exposure is an unavoidable risk associated with drug therapies in pregnant subjects. The role of metabolism, via phase I and II pathways, in regulating fetal exposure is relatively lesser known. Fetal metabolism and the presence of cytochromes P450 (P450s) in the fetal liver have been previously documented in the literatur