Pharmacokinetic studies of enalaprilat in the in vitro perfused human placental lobule system

Abstract

The objectives of this study were to evaluate the transplacental kinetics and effects on placental function of the angiotensin converting enzyme (ACE) inhibitor, enalaprilat, in the dually perfused human placental lobule system. When placed in the maternal perfusate at a high therapeutic serum concentration (150 ng/ml), enalaprilat was rapidly transferred from the maternal perfusate into placental tissue followed by a gradual release from the placenta into the fetal perfusate. Cmax and AUC values for enalaprilat in the maternal perfusate were approximately 3 times higher than in the fetal perfusate, and drug levels did not equilibrate between maternal and fetal perfusates during the 4-6 hours of perfusion. The more highly perfused regions of the placental lobule had higher drug levels than non-perfused areas. At the end of the perfusion period, the mean percent of total drug added in the maternal perfusate was 59%, with 23% in the fetal perfusate and the remainder (18%) in placental tissue. Despite the relatively high levels of drug found in placental tissue, there were no alterations in placental function as measured by fetal volume loss, fetal pressure, glucose utilization, lactate production, hCG release, net fetal oxygen transfer, and oxygen consumption. Results from this study clearly document placental transfer of enalaprilat in the perfused human placental lobule system. The lack of effect on placental function suggests that enalaprilat has no direct effect on fetoplacental vascular beds, and that fetal hypotension occurring from ACE inhibitor exposure may be due to direct effects on the fetal kidney and not to decreased perfusion of fetoplacental vascular beds; these findings require further validation in an in vivo model.