Metabolism of 17alpha-hydroxyprogesterone caproate, an agent for preventing preterm birth, by fetal hepatocytes.
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, 17alpha-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.
Sharma
Shringi
S
Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Ellis
Ewa C S
EC
Dorko
Kenneth
K
Zhang
Shimin
S
Mattison
Donald R
DR
Caritis
Steve N
SN
Venkataramanan
Raman
R
Strom
Stephen C
SC
D000077713:17 alpha-Hydroxyprogesterone Caproate; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D055162:Biocatalysis; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D004965:Estrogen Antagonists / Q000378:metabolism / Q000627:therapeutic use; D005260:Female; D005333:Fetus / Q000166:cytology* / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D006908:Hydroxyprogesterones / Q000378:metabolism* / Q000627:therapeutic use; D007313:Insecta / Q000166:cytology; D007700:Kinetics; D008861:Microsomes / Q000378:metabolism; D011247:Pregnancy; D047928:Premature Birth / Q000517:prevention & control; D014162:Transfection
D004965:Estrogen Antagonists; D006908:Hydroxyprogesterones; D000077713:17 alpha-Hydroxyprogesterone Caproate; D001189:Aryl Hydrocarbon Hydroxylases; C103123:CYP3A7 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human