Influence of Changes in Physiology, Transporters, and Enzyme Expression on Disposition and Metabolism of Drugs during Pregnancy and Clinical Implications

Safe and effective administration of drugs during pregnancy is a challenge due to physiological changes in the mother and limited development of the mechanisms of metabolism of xenobiotics in the fetus. In particular, concentrations of transporters such as PgP, BCRP, MRP3, OCT3, and OCTN1 change in the mother's placenta and fetal tissues with advancing gestation, confounding standard therapies. Drug-metabolizing enzymes in the placenta and developing fetus differ from those in the liver of the mother. For example, CYP3A7 is the predominant CYP3A isoform in the fetus, while CYP3A4 is predominant in adults. These isoforms have different substrates and kinetics, and thus, challenges to the fetus can be very different. Hence, there is a need for selectivity in administration of drugs and for titrating the dose to maintain efficacy and/or minimize side effects during pregnancy. This is particularly important for drugs with a narrow therapeutic window or those with marked pharmacologic or toxicological outcomes, and also for drugs that are metabolized predominantly by a single enzyme or transporter. Before initiating any new drug regimen during pregnancy, there is the need for systemic monitoring of plasma concentrations for exposure, especially during the initial days of therapy. It is anticipated that with the advancement of understanding of drug metabolism and transport in the placenta and fetus, the potential for making early predictions with respect to effect and tolerance of drugs may be possible, resulting in safer drug therapies for both pregnant mothers and fetus. Keywords: pregnancy; fetus; placenta; drug metabolism; transport