Molecular basis of altered drug metabolism during pregnancy

超过50%的孕妇服用一种或多种处方药，但有关安全性的数据有限， 怀孕期间使用的大多数药物的疗效和药代动力学(PKs)。积累证据 表明药物处置在怀孕期间由于广泛的生理变化而改变， 包括肝脏药物代谢的变化率。对于大多数药物，非怀孕妇女使用的剂量不能 被推断为怀孕。然而，一直缺乏针对孕妇的剂量指南，主要是因为 目前对妊娠期改变药物处置的理解是不完整的。这随后导致了 增加孕妇服药过多或服药不足的风险，使胎儿暴露在 药物不良反应或母体疾病。深入了解药物在使用过程中的PK变化 怀孕和导致这些变化的因素是实现最佳药物治疗的关键 怀孕了。我们研究的长期目标是为PK的预测建立坚实的知识基础 孕妇最佳个体化给药方案的设计与变化。这样做的目的是 应用是提供对细胞色素P450(CYP)改变药物代谢的机制的理解 2D6和CYP3A4，并将这些发现转化为人类怀孕。CYP2D6和CYP3A4是最多的两种 重要的药物代谢酶，共同负责代谢约70%的上市药物。 临床数据表明，在足月妊娠时，由CYP3A4或CYP2D6代谢的药物排出较快 (与产后相比)，但潜在的机制仍不清楚。在之前的研究中，我们 建立模型来研究DME在整个妊娠过程中的表达调节和识别因素 在妊娠期诱导细胞色素P450-2D6。具体地说，我们的结果表明，较低的肝脏维甲酸 转录因子(即SHP)的表达水平和随后的表达减少与CYP2D6有关 孕期引产。此外，来自人类肝细胞的结果表明，CYP3A4介导的药物 新陈代谢在怀孕早期最高(与怀孕或产后的后期相比 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)阐明孕期诱导CYP2D6的详细分子机制；(2) 明确导致孕期细胞色素P3A4介导的药物代谢时间变化的因素。至 为此，我们将进行从体外/动物研究到人类临床PK研究、测试等各种研究 将体外或动物研究结果转化为人类怀孕。预计结果将产生积极的影响 为预测CYP2D6或CYP3A4底物的PK奠定基础，并指导个体化 对孕妇的剂量建议。

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.