Molecular basis of altered drug metabolism during pregnancy

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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.