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首页> 外文期刊>Life sciences >Metabolism of medroxyprogesterone acetate (MPA) via CYP enzymes in vitro and effect of MPA on bleeding time in female rats in dependence on CYP activity in vivo.
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Metabolism of medroxyprogesterone acetate (MPA) via CYP enzymes in vitro and effect of MPA on bleeding time in female rats in dependence on CYP activity in vivo.

机译：乙酸甲羟孕酮（CYP）的体外代谢和取决于体内CYP活性的MPA对雌性大鼠出血时间的影响。

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Medroxyprogesterone acetate (MPA) is a drug commonly used in endocrine therapy for advanced breast cancer, although it is known to cause thrombosis as a serious side effect. Recently, we found that cytochrome P450 3A4 (CYP3A4) mainly catalyzed the metabolism of MPA via CYP in human liver microsomes. However, the metabolic products of MPA in humans and rats have not been elucidated. In addition, it is not clear whether thrombosis could be induced by MPA itself or by its metabolites. In this study, we determined the overall metabolism of MPA as the disappearance of the parent drug from an incubation mixture, and identified the enzymes catalyzing the metabolism of MPA via CYP in rats. Moreover, the effects of CYP-modulators on MPA-induced hypercoagulation in vivo were examined. Intrinsic clearance of MPA in rat liver microsomes was increased by treatment with CYP3A-inducers. The intrinsic clearance of MPA in liver microsomes of rats treated with various CYP-inducers showed a significant correlation with CYP3A activity, but not CYP1A activity, CYP2B activity or CYP2C contents. Among the eight recombinant rat CYPs studied, CYP3A1, CYP3A2 and CYP2A2 catalyzed the metabolism of MPA. However, since CYP3A2 and CYP2A2 are male-specific isoforms, CYP3A1 appears to be mainly involved in the metabolism of MPA in liver microsomes of female rats. In an in vivo study, pretreatment of female rats with SKF525A, an inhibitor of CYPs including CYP3A1, significantly (p < 0.05) enhanced MPA-induced hypercoagulation, whereas pretreatment with phenobarbital, an inducer of CYPs including CYP3A1, reduced it. These findings suggest that CYP-catalyzed metabolism of MPA is mainly catalyzed by CYP3A1 and that MPA-induced hypercoagulation is predominantly caused by MPA itself in female rats.
机译：醋酸甲羟孕酮（MPA）是晚期乳腺癌的内分泌治疗中常用的药物，尽管已知它会导致血栓形成，并具有严重的副作用。最近，我们发现细胞色素P450 3A4（CYP3A4）主要通过CYP催化人肝微粒体中MPA的代谢。然而，尚未阐明人和大鼠中MPA的代谢产物。此外，尚不清楚MPA本身或其代谢产物是否可引起血栓形成。在这项研究中，我们确定了MPA的整体代谢是母体药物在孵育混合物中的消失，并确定了通过CYP催化大鼠中MPA代谢的酶。此外，检查了CYP调节剂对MPA诱导的体内高凝的影响。 CYP3A诱导剂治疗可增加大鼠肝微粒体中MPA的内在清除率。用各种CYP诱导剂处理的大鼠肝微粒体中MPA的固有清除率与CYP3A活性显着相关，但与CYP1A活性，CYP2B活性或CYP2C含量无关。在所研究的八种重组大鼠CYP中，CYP3A1，CYP3A2和CYP2A2催化MPA的代谢。然而，由于CYP3A2和CYP2A2是雄性特异性同工型，因此CYP3A1似乎主要参与雌性大鼠肝微粒体中MPA的代谢。在一项体内研究中，用CYP抑制剂（包括CYP3A1）对SKF525A雌性大鼠进行的预处理显着（p <0.05）增强了MPA诱导的高凝，而用苯巴比妥（CYPs包括CYP3A1的诱导剂）进行的预处理则降低了MPA诱导的高凝。这些发现表明，CYP催化的MPA代谢主要由CYP3A1催化，而MPA诱导的高凝主要是由MPA本身在雌性大鼠中引起的。

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