Altered drug metabolism in pregnancy

妊娠期药物代谢的改变

• 批准号: 8075216
• 负责人: Hyunyoung Jeong
• 金额: $ 35.32万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8075216
• 关键词: Accounting; Aftercare; Area; Behavior; Biological Assay; Biological Models; CYP1A2 gene; CYP2D6 gene; CYP3A4 gene; Cells; Clinical; Complex; Cytochrome P450; Data; Deletion Mutation; Dose; Drug Exposure; Drug Kinetics; Drug Prescriptions; Elements; Enzymes; Estradiol; Estriol; Estrogen Receptors; Estrogens; Estrone; Exposure to; Female; Fetus; Genes; Genome; Health; Hepatic; Hepatocyte; Hormones; Human; Incubated; Knowledge; Laboratories; Ligand Binding; Ligands; Messenger RNA; Monitor; Mothers; Oral Contraceptives; Patients; Personal Satisfaction; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Physiology; Plasma; Population; Pregnancy; Pregnant Women; Production; Progesterone; Proteins; Regimen; Regulation; Reporter; Reporting; System; Testing; Time; Transgenic Mice; Up-Regulation; Western Blotting; Woman; Women' s Group; Work; chromatin immunoprecipitation; cytochrome P-450 CYP2A6 (human); drug metabolism; knock-down; men; pregnane X receptor; pregnant; promoter

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.

描述（由申请人提供）：超过50%的孕妇服用至少一种处方药。药物选择、剂量和监测对所有患者都很重要。然而，妊娠期间生理变化的复杂性以及药物治疗对孕妇和发育中的胎儿的健康和福祉的影响使妊娠期间的治疗复杂化。临床证据告诉我们，妊娠会改变肝脏药物代谢，但导致这一现象的致病因素仍有待确定。妊娠增加了细胞色素P450（CYP）2A 6、-2C9、-2D6或-3A4底物药物的消除，同时减少了CYP 1A 2或-2C19底物的消除。在与怀孕有关的生理变化中，最显著的是雌性激素的产生急剧增加，即，雌激素和孕酮（PRG）。我们实验室的初步结果表明，在人肝细胞中，雌二醇（E2）调节CYP 1A 2和-2A6的表达，而PRG上调CYP 2A 6和-3A4。对于这些β-内酰胺酶，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间药物代谢变化的部分原因。值得注意的是，E2和PRG并不能概括妊娠期间药物代谢的所有变化，例如诱导CYP 2D 6活性。这表明，目前未知的因素调节在怀孕期间的表达。我们实验室的初步数据表明，孕妇血浆中存在这些因子。该项目的中心假设是，伴随妊娠的生理变化调节了β表达，导致药物代谢改变。具体目标如下：（1）研究雌激素对药物代谢和表达的联合作用。(2)阐明PRG诱导CYP 3A 4的调节机制。(3)确定妊娠期间CYP 2D 6诱导的调节机制。(4)使用在孕妇血浆中孵育的人肝细胞建立模型系统以研究妊娠期间药物代谢的改变。拟议的研究将使我们能够识别和表征妊娠相关因素，这些因素是导致妊娠期间药物代谢改变的原因，确定它们对CYP 2D 6和CYP 3A 4表达的影响，并确定两种临床上最重要的CYP 2D 6和CYP 3A 4的潜在调控机制。妊娠期间复杂的生理变化和药物暴露于母亲及其发育中的胎儿的后果强调了阐明妊娠期间药物代谢调节的潜在机制的重要性。我们在这方面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。这些信息将对妊娠期间的药物选择和给药产生有价值的影响。 公共卫生相关性：孕妇使用药物是常见的，这一人群的药物行为通常与非孕妇或男性不同。了解这些变化对于确定最佳给药方案非常重要。我们建议调查是什么原因引起的药物行为的变化，并研究潜在的机制。从这项研究中获得的知识可以扩展到优化其他妇女群体的药物治疗，如口服避孕药使用者，从而使广大妇女受益。