124: Metabolism of 17-hydroxyprogesterone caproate by human hepatic and placental microsomes

Abstract

PLACENTAL MICROSOMES RU YAN, TATIANA NANOVSKAYA, DONALD MATTISON, GARY D.V. HANKINS, MAHMOUD AHMED, University of Texas Medical Branch, Obstetrics and Gynecology, Galveston, Texas, Obstetric-Fetal Pharmacology Research Units (OPRU) Network, Center for Research For Mother and Children NICHD, Bethesda, MD, Bethesda, Maryland OBJECTIVE: Administration of 17 -hydroxyprogesteronecaproate (17-P) is associated with prevention of preterm deliveries in 30% of the patients. However, the mechanism of action of 17-P and whether it is a drug or prodrug remains unclear. Recently, we demonstrated that 17-P is not hydrolyzed by human hepatic and placental homogenates. The aim of this investigation is to determine whether 17-P is metabolized by human hepatic and placental microsomes by a pathway that does not involve its hydrolysis by esterases. STUDY DESIGN: Crude microsomal fractions from human livers and term placentas were ued. A dual radioactive labeled 17 -[3H]-hydroxy progestrone [14 C]-caproate was utilized. The metabolites formed were separated and identified by HPLC/MS and their amounts determined by scintillation spectrometry. RESULTS: Hepatic and placental microsomes catalyzed the formation of several hydroxylated derivatives of 17-P that retained the tritium and 14C atoms. In human liver, the metabolites formed were divided into the following three groups according to the extent of their hydroxylation as revealed by their mass: mono-, diand tri-hydroxylated 17-P which accounted for 63, 37 and 1% of the total formed, respectively. The major mono-hydroxylated compound formed by the liver accounted for 38% of the total metabolites formed. In human placenta, only monohydroxylated metabolites were formed. Two of these metabolites accounted for 16% of the total and were not formed by hepatic microsomes. The rates of metabolites formation by the placenta were approximately 7% of that by the liver. CONCLUSION: Human liver CYP isozymes metabolize 17-P to mono-, diand tri-hydroxylated compounds while in the placenta only mono-hydroxylated compounds are formed. Two of the metabolites formed by the placenta are not formed by the liver. At this time, it is unclear whether one or more of 17-P metabolites could contribute to its reported physiological effect. Supported by the Obstetric Pharmacology Research Network (OPRU/NICHD).