Molecular basis of altered drug metabolism during pregnancy

超过50%的孕妇服用一种或多种处方药，但关于安全性的数据有限， 妊娠期间使用的大多数药物的疗效和药代动力学（PK）。越来越多的证据 表明药物处置在妊娠期间由于广泛的生理变化而改变， 包括肝脏药物代谢率的改变。对于大多数药物，非妊娠妇女使用的剂量不能 可以推断为怀孕。然而，孕妇的剂量指南一直缺乏，主要是因为 目前对妊娠期间药物处置改变的了解尚不完整。随后，这导致 孕妇过量或剂量不足的风险增加，胎儿暴露于 药物不良反应或母体疾病。深入了解药物在治疗期间的PK变化 怀孕和负责的变化的因素是当务之急，以实现最佳的药物治疗期间， 怀孕我们研究的长期目标是为PK的预测建立一个坚实的知识基础 变化和设计最佳的个性化剂量方案为孕妇。这一目标 应用是提供细胞色素P450（CYP）改变药物代谢的机制理解 2D 6和CYP 3A 4，并将这些发现转化为人类妊娠。CYP 2D 6和CYP 3A 4是最常见的两种。 重要的药物代谢酶，共同负责代谢约70%的市售药物。 临床数据表明，经CYP 3A 4或CYP 2D 6代谢的药物在足月妊娠时消除更快 (as与产后期相比），但潜在的机制仍不清楚。在以前的研究中，我们 建立模型研究DME在整个妊娠期的表达调控，并确定影响DME表达的因素 在妊娠期间促进CYP 2D 6诱导。具体来说，我们的研究结果表明， 水平和随后的转录因子表达的降低（即，SHP）参与CYP 2D 6 怀孕期间的引产。此外，人肝细胞的结果表明，CYP 3A 4介导的药物 在怀孕早期代谢最高（与怀孕或产后的后期时间点相比 期间），可能是由于甲状腺激素浓度的变化。根据这些结果，我们建议： (1)阐明妊娠期间CYP 2D 6诱导的详细分子机制，和（2） 定义导致妊娠期间CYP 3A 4介导的药物代谢时间变化的因素。到 为此，我们将进行从体外/动物研究到人体临床PK研究的研究， 将体外或动物发现转化为人类妊娠。结果预计将有积极的 通过为CYP 2D 6或CYP 3A 4底物的PK预测奠定基础，指导个体化 给孕妇的剂量建议。

Over 50% of pregnant women take one or more prescription drugs, but there are limited data on the safety, efficacy and pharmacokinetics (PKs) of the majority of drugs used during pregnancy. Accumulating evidence indicates that drug disposition is altered during pregnancy due to the extensive physiological changes, including altered rate of hepatic drug metabolism. For most drugs, doses used in non-pregnant women cannot be extrapolated to pregnancy. Yet, dosing guidelines for pregnant women have been lacking, mainly because current understanding about altered drug disposition during pregnancy is incomplete. This subsequently leads to an increased risk for over- or under-dosing of drugs in pregnant women and exposure of her fetus to either adverse drug effects or maternal disease. Thorough understanding of the PK changes of drugs during pregnancy and factors responsible for the changes is imperative to achieve optimal drug therapy during pregnancy. The long-term goal of our research is to build a solid knowledge base for the prediction of PK changes and the design of optimal individualized dosage regimens for pregnant women. The objectives of this application are to provide mechanistic understanding of altered drug metabolism by cytochrome P450 (CYP) 2D6 and CYP3A4 and to translate the findings to human pregnancy. CYP2D6 and CYP3A4 are the two most important drug-metabolizing enzymes and together responsible for metabolizing ~70% of marketed drugs. Clinical data indicate that elimination of drugs metabolized by CYP3A4 or CYP2D6 is faster at term pregnancy (as compared to postpartum period), but underlying mechanisms remain unclear. In previous studies, we established models to study regulation of DME expression throughout gestation and identified factors contributing to CYP2D6 induction during pregnancy. Specifically, our results suggest that lower hepatic retinoid level and subsequent decreases in the expression of a transcription factor (i.e., SHP) are involved in CYP2D6 induction during pregnancy. Also, results from human hepatocytes suggest that CYP3A4-mediated drug metabolism is highest during early pregnancy (compared to the later time points of pregnancy or postpartum period), potentially due to changes in thyroid hormone concentration. Based on these results, we propose to: (1) elucidate the detailed molecular mechanisms underlying CYP2D6 induction during pregnancy, and (2) define factors responsible for temporal changes in CYP3A4-mediated drug metabolism during pregnancy. To this end, we will perform studies ranging from in vitro/animal studies to human clinical PK studies, testing translation of in vitro or animal findings to human pregnancy. The results are expected to have a positive impact by laying a foundation for PK prediction of CYP2D6 or CYP3A4 substrates and guide individualized dosing recommendations for pregnant women.