Illicit drug use during pregnancy is a major risk factor for maternal and fetal morbidity. In addition, licit drugs are routinely administered to pregnant women, and therefore their fetuses, without the necessary data about the pharmacokinetics of these drugs in these vulnerable populations. The overall goal of this POI is to make use of drugs during pregnancy efficacious (licit drugs) and safer (licit and illicit drugs). We will achieve thi goal by testing the following overarching and unifying central hypothesis: Expression and activity of hepatic cytochrome P450 enzymes and placental drug transporters during pregnancy are regulated by pregnancy- related hormones and/or growth factors and by exposure to drugs and xenobiotics. Elucidating these mechanisms and quantifying the pregnancy-induced changes in these CYP and transporter activities will allow PBPK prediction of changes in maternal-fetal exposure to drugs througout pregnancy. The P450 enzymes and transporters we will study are those likely to be quantitatively most important for metabolism and transport of both illicit and licit drugs in the liver or the placenta, namely CYP3A (Project 1), CYP2B6 and CYP2D6 (Project 2), P-gp and BCRP (Project 3), and OCTS, NET, and SERT (Project 4). Pregnancy is known to induce expression and activity of hepatic CYP3A and CYP2D6, thus possibly lowering maternal exposure to drugs and potentially decreasing their efficacy. In the placenta, P-gp and BCRP participate in the efflux of drugs from the fetal compartment to the maternal circulation, thus protecting the fetus from adverse effects of drugs, while 0CT3, NET and/or SERT function to allow the entry of potentially toxic drugs into the fetal circulation. Thi POI uses a collaborative, synergistic, multidisciplinary and systems pharmacology approach to test the above-stated hypothesis. Results obtained from the proposed studies will allow us to predict how maternal and fetal exposure to licit and illicit drugs is affected by pregnancy and by gestational age and will reveal interesting and potentially novel mechanisms on physiological regulation of CYPs and transporters studied.

Public Health Relevance

Results obtained from the studies proposed here will allow us to make rational decision on licit drug use during pregnancy and will allow assessment of the potential risk to the fetus of maternal use of illicit drugs. This assessment will be based on mechanistic understanding of drug disposition in pregnancy rather than on an empirical risk-benefit ratio. DESCRIPTION (provided by applicant): Illicit drug use during pregnancy is a major risk factor for maternal and fetal morbidity. In addition, licit drugs are routinely administered to pregnant women, and therefore their fetuses, without the necessary data about the pharmacokinetics of these drugs in these vulnerable populations. The overall goal of this POI is to make use of drugs during pregnancy efficacious (licit drugs) and safer (licit and illicit drugs). We will achieve thi goal by testing the following overarching and unifying central hypothesis: Expression and activity of hepatic cytochrome P450 enzymes and placental drug transporters during pregnancy are regulated by pregnancy- related hormones and/or growth factors and by exposure to drugs and xenobiotics. Elucidating these mechanisms and quantifying the pregnancy-induced changes in these CYP and transporter activities will allow PBPK prediction of changes in maternal-fetal exposure to drugs througout pregnancy. The P450 enzymes and transporters we will study are those likely to be quantitatively most important for metabolism and transport of both illicit and licit drugs in the liver or the placenta, namely CYP3A (Project 1), CYP2B6 and CYP2D6 (Project 2), P-gp and BCRP (Project 3), and OCTS, NET, and SERT (Project 4). Pregnancy is known to induce expression and activity of hepatic CYP3A and CYP2D6, thus possibly lowering maternal exposure to drugs and potentially decreasing their efficacy. In the placenta, P-gp and BCRP participate in the efflux of drugs from the fetal compartment to the maternal circulation, thus protecting the fetus from adverse effects of drugs, while 0CT3, NET and/or SERT function to allow the entry of potentially toxic drugs into the fetal circulation. Thi POI uses a collaborative, synergistic, multidisciplinary and systems pharmacology approach to test the above-stated hypothesis. Results obtained from the proposed studies will allow us to predict how maternal and fetal exposure to licit and illicit drugs is affected by pregnancy and by gestational age and will reveal interesting and potentially novel mechanisms on physiological regulation of CYPs and transporters studied.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Program Projects (P01)
Project #
4P01DA032507-04
Application #
9069781
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Rapaka, Rao
Project Start
2013-09-01
Project End
2018-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Washington
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Han, Lyrialle W; Gao, Chunying; Mao, Qingcheng (2018) An update on expression and function of P-gp/ABCB1 and BCRP/ABCG2 in the placenta and fetus. Expert Opin Drug Metab Toxicol 14:817-829
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Grant, Kimberly S; Petroff, Rebekah; Isoherranen, Nina et al. (2018) Cannabis use during pregnancy: Pharmacokinetics and effects on child development. Pharmacol Ther 182:133-151
Wagner, David J; Shireman, Laura M; Ahn, Sojung et al. (2018) Disposition of Methamphetamine and Major Metabolites in Mice: Role of Organic Cation Transporter 3 in Tissue-Selective Accumulation of Para-Hydroxymethamphetamine. Drug Metab Dispos 46:1277-1284
Wagner, David J; Sager, Jennifer E; Duan, Haichuan et al. (2017) Interaction and Transport of Methamphetamine and its Primary Metabolites by Organic Cation and Multidrug and Toxin Extrusion Transporters. Drug Metab Dispos 45:770-778

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