RT Journal Article
SR Electronic
T1 Metabolism of 17α-Hydroxyprogesterone Caproate, an Agent for Preventing Preterm Birth, by Fetal Hepatocytes
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 723
OP 727
DO 10.1124/dmd.109.029918
VO 38
IS 5
A1 Shringi Sharma
A1 Ewa C. S. Ellis
A1 Kenneth Dorko
A1 Shimin Zhang
A1 Donald R. Mattison
A1 Steve N. Caritis
A1 Raman Venkataramanan
A1 Stephen C. Strom
YR 2010
UL http://dmd.aspetjournals.org/content/38/5/723.abstract
AB Preterm delivery (i.e., delivery before 37 completed weeks of gestation) 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, 17α-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 metabolism 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 expressed 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 metabolite. 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. U.S. Government work not protected by U.S. copyright