Metabolism of 17alpha-hydroxyprogesterone caproate by hepatic and placental microsomes of human and baboons.
Metabolism of 17alpha-hydroxyprogesterone caproate by hepatic and placental microsomes of human and baboons.
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人类和狒狒的肝脏和胎盘微粒体对 17α-羟基孕酮己酸酯的代谢。
DOI：
10.1016/j.bcp.2008.01.013
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发表时间：
2008
影响因子：
5.8
通讯作者：
Ahmed,MahmoudS
中科院分区：
文献类型：
--
作者：
Yan,Ru;Nanovskaya,TatianaN;Zharikova,OlgaL;Mattison,DonaldR;Hankins,GaryDV;Ahmed,MahmoudS
我们实验室最近的数据显示，用于治疗早产的17-羟孕酮己酸酯（17- hpc）在双灌注人胎盘小叶灌注过程中形成了一种未知的代谢物。在此之前，我们证明了该药物在体内和体外都不会水解为黄体酮和己酸盐。因此，本研究的假设是17-HPC被人和狒狒（Papio cynocephalus）的肝脏和胎盘微粒体积极代谢。研究了狒狒肝脏和胎盘微粒体，以验证非人灵长类动物作为怀孕期间药物使用的动物模型。这里的数据表明，人和狒狒的肝微粒体形成了几种17-HPC的单羟基、二羟基和三羟基衍生物。然而，人类和狒狒胎盘微粒体将17-HPC代谢为其单羟基化衍生物的数量仅为其各自肝脏形成的数量的一小部分，除了胎盘特有的两种代谢物（M16 ‘和M17 ’），它们分别占人类和狒狒形成的总代谢物的25%和75%。人和狒狒微粒体形成的代谢物的相对数量不同，这表明17-HPC对CYP酶的亲和力及其活性可能是物种依赖性的。
Recent data from our laboratory revealed the formation of an unknown metabolite of 17 hydroxyprogesterone caproate (17-HPC), used for treatment of preterm deliveries, during its perfusion across the dually perfused human placental lobule. Previously, we demonstrated that the drug is not hydrolyzed, neither in vivo nor in vitro, to progesterone and caproate. Therefore, the hypothesis for this investigation is that 17-HPC is actively metabolized by human and baboon (Papio cynocephalus) hepatic and placental microsomes. Baboon hepatic and placental microsomes were investigated to validate the nonhuman primate as an animal model for drug use during pregnancy. Data presented here indicate that human and baboon hepatic microsomes formed several mono-, di-, and tri-hydroxylated derivatives of 17-HPC. However, microsomes of human and baboon placentas metabolized 17-HPC to its mono-hydroxylated derivatives only in quantities that were a fraction of those formed by their respective livers, except for two metabolites (M16′ and M17′) that are unique for placenta and contributed to 25% and 75% of the total metabolites formed by human and baboon, respectively. The amounts of metabolites formed, relative to each other, by human and baboon microsomes were different suggesting that the affinity of 17-HPC to CYP enzymes and their activity could be species-dependent.