Cytochrome P450 3A4/5 enzymes (CYP3A4/5) collectively metabolize more drugs (licit and illicit) than any other cytochrome P450 enzymes (e.g. HIV protease inhibitors, methadone, cocaine). ? Our laboratory has found that CYPSA activity is elevated during late pregnancy in both women and mice (including in transgenic mice expressing the CYP3A4-promoter luciferase construct, Tg mice). While these data provide guidance on dose adjustment of CYPSA metabolized drugs during the Srd trimester, due to ethical and logistical reasons, no such data are available to guide dosing of CYPSA metabolized drugs during the 1st and 2nd trimesters. Therefore, our specific aims are to determine: la) if human hepatocytes exposed to Srd trimester plasma hormone concentrations can quantitatively replicate the in vivo induction of CYPSA (and other CYP) enzymes during the 3rd trimester: and lb) whether human hepatocytes can be used to predict the magnitude of change in in vivo hepatic CYPSA (and other CYP) activity in the 1st and 2nd trimester. To determine the mechanisms by which pregnancy induces CYPS/VCypSa activity, we will pursue the following specific aims: 2) We will confirm that placental growth hormone (or mouse growth hormone), progesterone, Cortisol (corticosterone) or estradiol, at their physiological concentrations observed during late mouse or human pregnancy, produce comparable induction of hepatic luciferase, CypSa activity and CypSa mRNA in hepatocytes from female Tg mice of reproductive age; S) Using the combination of hormones identified in Aims la and 2 above, we will determine its ability, after chronic administration, to induce hepatic luciferase, CypSa activity and CypSa mRNA expression, in vivo, in non-pregnant female Tg mice (i.e. pseudopregnancy studies); 4) To determine if the hormones in Aim S induce CypS/VSa enzymes via their receptors, we will determine their ability to induce CypSA/Sa activity and expression in: a) Human hepatocytes where their receptors (e.g. GR) have been knocked-down by siRNA technology; b) The most appropriate hepatic specific null receptor pregnant mice (e.g. GR(-/-) or GHR/GR(-/-)) as determined by results obtained from Aim 4a.

Public Health Relevance

Completion of this project will allow the clinician to predict the magnitude of maternal-fetal exposure to CYPSA-metabolized drugs (both licit and illicit) throughout pregnancy and, therefore, devise dosing regimens of such licit drugs that maximize their efficacy and minimize their toxicity. In addition, our proposed studies will begin to unravel the mechanisms by which CYPSA activity is induced by pregnancy.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-DKUS-C)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Washington
Domestic Higher Education
United States
Zip Code
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
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
Patilea-Vrana, Gabriela I; Unadkat, Jashvant D (2018) When Does the Rate-Determining Step in the Hepatic Clearance of a Drug Switch from Sinusoidal Uptake to All Hepatobiliary Clearances? Implications for Predicting Drug-Drug Interactions. Drug Metab Dispos 46:1487-1496
Kumar, Vineet; Yin, Jia; Billington, Sarah et al. (2018) The Importance of Incorporating OCT2 Plasma Membrane Expression and Membrane Potential in IVIVE of Metformin Renal Secretory Clearance. Drug Metab Dispos 46:1441-1445
Neradugomma, Naveen K; Drafton, Kaitlyn; O'Day, Diana R et al. (2018) Marijuana use differentially affects cannabinoid receptor expression in early gestational human endometrium and placenta. Placenta 66:36-39
Liao, Michael Z; Gao, Chunying; Phillips, Brian R et al. (2018) Pregnancy Increases Norbuprenorphine Clearance in Mice by Induction of Hepatic Glucuronidation. Drug Metab Dispos 46:100-108
Guo, Yingying; Chu, Xiaoyan; Parrott, Neil J et al. (2018) Advancing Predictions of Tissue and Intracellular Drug Concentrations Using In Vitro, Imaging and Physiologically Based Pharmacokinetic Modeling Approaches. Clin Pharmacol Ther 104:865-889
Johnson, Emily J; González-Peréz, Vanessa; Tian, Dan-Dan et al. (2018) Selection of Priority Natural Products for Evaluation as Potential Precipitants of Natural Product-Drug Interactions: A NaPDI Center Recommended Approach. Drug Metab Dispos 46:1046-1052
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

Showing the most recent 10 out of 29 publications