Altered drug metabolism in pregnancy

说明(申请人提供)：超过50%的孕妇服用至少一种处方药。药物的选择、剂量和监测对所有患者都很重要。然而，怀孕期间复杂的生理变化，以及药物治疗对孕妇和发育中胎儿的健康和福祉的影响，使怀孕期间的治疗变得复杂。临床证据告诉我们，妊娠改变了肝脏的药物代谢，但导致这种现象的原因尚不清楚。怀孕会增加细胞色素P450(CYP)2A6、-2C9、-2D6或-3A4底物药物的消除，而减少细胞色素P1A2或-2C19底物的消除。在与怀孕相关的生理变化中，最明显的是女性荷尔蒙的产生急剧增加，即雌激素和孕酮(PRG)。本实验室的初步研究结果表明，雌二醇(E_2)可调节人肝细胞中细胞色素P450_(1A2)和-2A6的表达，而黄体生成素(PRG)则可上调肝细胞中的细胞色素P450_2A_2和-3A_4的表达。对于这些CYP酶，其表达的方向性变化与临床报道的药代动力学变化相似，表明女性激素可能是妊娠期药物代谢变化的部分原因。值得注意的是，E2和PRG不能概括妊娠期间药物代谢的所有变化，例如诱导CYP2D6活性。这表明，目前尚不清楚的因素调节怀孕期间细胞色素P450的表达。我们实验室的初步数据表明，孕妇的血浆中存在这些因子。这个项目的中心假设是，伴随着怀孕的生理变化调节CYP的表达，导致药物代谢的改变。具体目标如下：(1)研究雌性激素对细胞色素P450表达和药物代谢的联合作用。(2)阐明PRG诱导细胞色素P3A4表达的调控机制。(3)明确孕期诱导细胞色素P450-2D6的调控机制。(4)建立孕期药物代谢变化的模型系统，利用孕妇血浆中培养的人肝细胞进行研究。这些拟议的研究将使我们能够识别和表征导致怀孕期间药物代谢改变的妊娠相关因素，建立它们对CYP表达的影响，并确定临床上最重要的两种CYP酶--CYP2D6和CYP3A4的潜在调节机制。孕期复杂的生理变化以及药物暴露给母亲和发育中的胎儿带来的后果，突显了阐明孕期药物代谢调节的潜在机制的重要性。我们在这一领域的初步工作和本文提出的研究将最终帮助我们准确预测药物在孕妇体内的药代动力学变化。这些信息将对怀孕期间的药物选择和剂量产生有价值的影响。 公共卫生相关性：孕妇使用药物是很常见的，这一人群的药物行为通常不同于非孕妇或男性。了解这些变化对于确定最佳给药方案很重要。我们建议调查是什么导致药物行为的变化，并研究其潜在的机制。从这项研究中获得的知识可以扩大到优化其他妇女群体的药物治疗，例如口服避孕药使用者，从而使一般妇女受益。

DESCRIPTION (provided by applicant): Greater than 50% of pregnant women take at least one prescription drug. Drug selection, dosing, and monitoring are important for all patients. However, the intricacies of physiological changes during pregnancy and the implications of drug therapy on the health and well-being of pregnant mothers and the developing fetus complicate treatments during gestation. Clinical evidence informs us that pregnancy alters hepatic drug metabolism, but the causative factors responsible for this phenomenon remain to be identified. Pregnancy increases elimination of cytochrome P450 (CYP)2A6, -2C9, -2D6, or -3A4 substrate drugs, while decreasing elimination of CYP1A2 or -2C19 substrates. Of the physiological changes associated with pregnancy, most pronounced is a dramatic increase in the production of female hormones, i.e., estrogens and progesterone (PRG). Preliminary results from our laboratory indicate that estradiol (E2) modulates expression of CYP1A2 and -2A6 whereas PRG upregulates CYP2A6 and -3A4 in human hepatocytes. For these CYP enzymes, the directional changes in their expression are similar to the clinically reported pharmacokinetic changes, suggesting that female hormones may be in part responsible for the changes in drug metabolism during pregnancy. Of note, E2 and PRG do not recapitulate all the changes in drug metabolism during pregnancy, such as induction of CYP2D6 activity. This indicates that as yet unknown factors regulate CYP expression during pregnancy. Preliminary data from our laboratory indicate presence of such factors in pregnant women's plasma. The central hypothesis of this project is that physiological changes accompanying pregnancy modulate CYP expression, leading to altered drug metabolism. The following specific aims are proposed: (1) Characterize combined effects of female hormones on CYP expression and drug metabolism. (2) Elucidate regulatory mechanisms for CYP3A4 induction by PRG. (3) Identify regulatory mechanisms for CYP2D6 induction during pregnancy. (4) Establish a model system to study altered drug metabolism during pregnancy, using human hepatocytes incubated in pregnant women's plasma. The proposed studies will enable us to identify and characterize pregnancy-relevant factors that are responsible for altered drug metabolism during pregnancy, establish their effects on CYP expression, and determine the underlying regulatory mechanisms for two clinically most important CYP enzymes, CYP2D6 and CYP3A4. The complex physiological changes during pregnancy and the consequences of drug exposure to mothers and their developing fetuses underscore the importance of elucidating potential mechanisms for the regulation of drug metabolism during pregnancy. Our preliminary work in this area and the studies proposed herein will ultimately help us accurately predict pharmacokinetic changes of drugs in pregnant women. This information will have a valuable impact on drug selection and dosing during pregnancy. PUBLIC HEALTH RELEVANCE: Medication use by pregnant women is common, and drug behaviors in this population are generally different from those in non-pregnant women or men. Understanding of these changes is important in determining optimal dosing regimen. We propose to investigate what causes the changes in drug behaviors and study the underlying mechanisms. The knowledge obtained from this study can be expanded to optimize drug therapy in other groups of women, such as oral contraceptive users, thus benefiting women in general.