; Illicit and licit drugs are routinely used during pregnancy without the necessary pharmacokinetics, efficacy, or safety data. P-gp and BCRP are the two major ABC efflux transporters in the placenta that limit fetal exposure to drugs. The levels of P-gp and BCRP in the placenta change with gestation; however, how the changes in transporter expression affect fetal drug exposure over gestation is still poorly understood. Thus, the goal of this project is to assess the role of placental P-gp and BCRP in fetal drug exposure over gestation and elucidate the mechanisms by which P-gp and BCRP in the placenta are regulated during pregnancy. We have shown that progesterone strongly induces BCRP in BeWo cells via progesterone receptor B (PRB). Another related and important, but yet unanswered question is whether expression and activity of placental P-gp and BCRP can be altered by exposure to drugs through inhibition or induction. We hypothesize that expression and activity of placental P-gp and BCRP change with gestation through regulation by pregnancy hormones, growth factors, and retinoic acid as well as by drugs and xenobiotics. To test these hypotheses, we propose the following specific aims. We will determine 1) the effects of drug-drug interactions on fetal exposure to a P-gp (norbuprenorphine), a BCRP (nitrofurantoin), or a dual P-gp/BCRP (bupropion) substrate in FVB mice at two different gestational ages with and without a P-gp (nelfinavir), a BCRP (pantoprazole), or a dual P-gp/BCRP (elacridar) inhibitor, respectively; 2) if/n vitro expression and activity of P-gp and BCRP in primary human trophoblasts (from early, mid, and term placenta) are altered by the treatment with PXR (e.g., HIV protease inhibitors, methadone, St John's wort, and buprenorphine), CAR (e.g., phenobarbital, phenytoin and diazepam), AhR (e.g., omeprazole and benezo[a]pyrene) or PPARy (e.g., some NSAIDs) ligands at clinically relevant plasma concentrations, and elucidate the mechanisms of changes in expression observed; 3a) if in vitro expression and activity of P-gp and BCRP in primary human trophoblasts (from early, mid, and term placenta) are regulated by pregnancy hormones (e.g., progesterone, 17|3-estradiol, Cortisol, placental growth hormone), growth factors (e.g., epidermal growth factor and insulin-like growth factors), and all-trans retinoic acid, individually and in combination, at plasma concentrations observed during pregnancy, and elucidate the mechanisms of changes in expression observed; 3b) if progesterone regulates In vivo expression and activity of placental Bcrpi through PRB. We will measure expression and in vivo activity of placental Bcrp1 in PRB-/- pregnant mice compared with those in wild-type pregnant mice.
Completion ofthe proposed studies will lead to a more comprehensive and advanced understanding ofthe mechanism by which fetal exposure to illicit and licit drugs is mediated by the ATP-binding cassette efflux drug transporters P-gp and BCRP in the placenta during pregnancy. Results obtained from these studies will help the clinicians and the regulators to optimize and better guide drug therapy in pregnant women.
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