Division of Systems Biology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, Arkansas (J.C.F., V.V., T.H., L.R., J.J.G., R.D.B., L.M.P., Q.S.); and Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland (J.P.H.)
Division of Systems Biology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, Arkansas (J.C.F., V.V., T.H., L.R., J.J.G., R.D.B., L.M.P., Q.S.); and Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland (J.P.H.).
Drug Metab Dispos. 2020 Jun;48(6):447-458. doi: 10.1124/dmd.119.089367. Epub 2020 Mar 19.
Safety assessments of new drug candidates are an important part of the drug development and approval process. Often, possible sex-associated susceptibilities are not adequately addressed, and better assessment tools are needed. We hypothesized that hepatic transcript profiles of cytochrome P450 (P450) enzymes can be used to predict sex-associated differences in drug metabolism and possible adverse events. Comprehensive hepatic transcript profiles were generated for F344 rats of both sexes at nine ages, from 2 weeks (preweaning) to 104 weeks (elderly). Large differences in the transcript profiles of 29 drug metabolizing enzymes and transporters were found between adult males and females (8-52 weeks). Using the PharmaPendium data base, 41 drugs were found to be metabolized by one or two P450 enzymes encoded by sexually dimorphic mRNAs and thus were candidates for evaluation of possible sexually dimorphic metabolism and/or toxicities. Suspension cultures of primary hepatocytes from three male and three female adult rats (10-13 weeks old) were used to evaluate the metabolism of 11 drugs predicted to have sexually dimorphic metabolism. The pharmacokinetics of the drug or its metabolite was analyzed by liquid chromatography/tandem mass spectrometry using multiple reaction monitoring. Of those drugs with adequate metabolism, the predicted significant sex-different metabolism was found for six of seven drugs, with half-lives 37%-400% longer in female hepatocytes than in male hepatocytes. Thus, in this rat model, transcript profiles may allow identification of potential sex-related differences in drug metabolism. SIGNIFICANCE STATEMENT: The present study showed that sex-different expression of genes coding for drug metabolizing enzymes, specifically cytochrome P450s, could be used to predict sex-different drug metabolism and, thus, provide a new tool for protecting susceptible subpopulations from possible adverse drug events.
新药候选物的安全性评估是药物开发和审批过程的重要组成部分。通常，可能的性别相关易感性没有得到充分解决，需要更好的评估工具。我们假设细胞色素 P450（P450）酶的肝转录谱可用于预测药物代谢和可能的不良反应中的性别相关差异。我们为 F344 大鼠生成了全面的肝转录谱，包括 9 个年龄段的雌雄大鼠，从 2 周龄（新生）到 104 周龄（老年）。在成年雄性和雌性大鼠之间发现了 29 种药物代谢酶和转运蛋白的转录谱存在很大差异（8-52 周）。使用 PharmaPendium 数据库，发现 41 种药物由两种性别差异的 mRNA 编码的一个或两个 P450 酶代谢，因此是评估可能的性别差异代谢和/或毒性的候选药物。使用来自 3 只成年雄性和 3 只成年雌性大鼠（10-13 周龄）的原代肝细胞悬浮培养物评估 11 种预测具有性别差异代谢的药物的代谢。使用液相色谱/串联质谱法（多重反应监测）分析药物或其代谢物的药代动力学。在具有足够代谢的药物中，发现 7 种药物中的 6 种存在预测的显著性别差异代谢，女性肝细胞中的半衰期比男性肝细胞长 37%-400%。因此，在这种大鼠模型中，转录谱可用于鉴定药物代谢中潜在的性别相关差异。意义：本研究表明，编码药物代谢酶（特别是细胞色素 P450）的基因的性别差异表达可用于预测性别差异代谢，并为保护易受影响的亚人群免受潜在不良药物事件提供新工具。
