Miller R K, Jessee L, Barrish A, Gilbert J, Manson J M
Department of Obstetrics/Gynecology, University of Rochester Medical Center, New York 14642-8668, USA.
Teratology. 1998 Sep-Oct;58(3-4):76-81. doi: 10.1002/(SICI)1096-9926(199809/10)58:3/4<76::AID-TERA2>3.0.CO;2-7.
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.
本研究的目的是在双灌注人胎盘小叶系统中评估血管紧张素转换酶（ACE）抑制剂依那普利拉的经胎盘动力学及其对胎盘功能的影响。当以高治疗血清浓度（150 ng/ml）置于母体灌注液中时，依那普利拉迅速从母体灌注液转移至胎盘组织，随后逐渐从胎盘释放至胎儿灌注液中。依那普利拉在母体灌注液中的Cmax和AUC值约为胎儿灌注液中的3倍，且在4 - 6小时的灌注过程中母体和胎儿灌注液中的药物水平未达到平衡。胎盘小叶中灌注程度较高的区域比未灌注区域的药物水平更高。在灌注期结束时，母体灌注液中添加的总药物的平均百分比为59%，胎儿灌注液中为23%，其余（18%）在胎盘组织中。尽管在胎盘组织中发现药物水平相对较高，但通过胎儿体积减少、胎儿压力、葡萄糖利用、乳酸产生、hCG释放、胎儿净氧转运和氧消耗来衡量，胎盘功能没有改变。本研究结果清楚地证明了依那普利拉在灌注人胎盘小叶系统中的胎盘转运。对胎盘功能缺乏影响表明依那普利拉对胎儿 - 胎盘血管床没有直接影响，并且ACE抑制剂暴露引起的胎儿低血压可能是由于对胎儿肾脏的直接作用，而不是胎儿 - 胎盘血管床灌注减少；这些发现需要在体内模型中进一步验证。
