Altered drug metabolism in pregnancy

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，怀孕期间生理变化的复杂性以及药物治疗对孕妇和胎儿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，妊娠改变了肝脏药物代谢，但导致这一现象的原因仍有待确定。妊娠增加细胞色素P450 (CYP)2A6、-2C9、-2D6或-3A4底物药物的消除，而减少CYP1A2或-2C19底物的消除。在与怀孕有关的生理变化中，最明显的是女性激素，即雌激素和黄体酮（PRG）的产生急剧增加。我们实验室的初步结果表明，雌二醇（E2）调节人肝细胞中CYP1A2和-2A6的表达，而PRG上调CYP2A6和-3A4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，提示女性激素可能对妊娠期间药物代谢的变化负有部分责任。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，如诱导CYP2D6活性。这表明尚不清楚的因素在妊娠期间调节CYP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素。这个项目的中心假设是，伴随怀孕的生理变化调节CYP的表达，导致药物代谢的改变。提出以下具体目标：(1)研究女性激素对CYP表达和药物代谢的联合作用。(2)阐明PRG诱导CYP3A4的调控机制。(3)明确妊娠期CYP2D6诱导的调控机制。(4)利用孕妇血浆培养的人肝细胞，建立研究妊娠期间药物代谢改变的模型系统。这些研究将使我们能够识别和表征妊娠期间药物代谢改变的妊娠相关因素，确定其对CYP表达的影响，并确定两种临床上最重要的CYP酶CYP2D6和CYP3A4的潜在调节机制。怀孕期间复杂的生理变化以及药物暴露对母亲及其发育中的胎儿的影响，强调了阐明怀孕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有重要影响。

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.