Pregnant women and their fetuses are therapeutic """"""""orphans."""""""" As recently stated by Dr. Kennedy of the FDA, now it's time to provide the best information we can for women who take drugs while they're pregnant."""""""" This SCOR application seeks to fulfill this national goal. Drugs are administered to pregnant women, and therefore their fetuses, without the necessary clinical data about the pharmacokinetics, dose, safety, or efficacy of the drugs in these vulnerable populations. To determine the correct dose of a drug to administer to the pregnant woman, it is important to know if the pharmacokinetics of the drug is different in pregnant women when compared with men or nonpregnant women. In this SCOR application we will focus on one of two major routes of drug disposition, namely drug transport. We will test the following overarching and unifying hypothesis: Expression and activity of influx and efflux transporters is upregulated during pregnancy to respectively meet the increased need of nutrients by the mother and her fetus and to minimize toxicity from xenobiotics. The transporters we will study are those likely to be quantitatively most important in drug transport in both the Intestine and the placenta, namely P-glycoprotein (P-gp; Project 1), the Breast Cancer Resistance Protein (BCRP; Project 2), and the Organic Cation Transporter 3 (OCT3; Project 3). In the placenta, P-glycoprotein and BCRP participate in the efflux of drugs, thus protecting the fetus from deleterious effects of drugs, while OCT3 functions to allow the entry of endogenous compounds (and drugs) into the fetal circulation. In contrast, all three transporters play a synergistic role in the elimination of drugs in the liver and intestine. Moreover, all three transporters have overlapping but distinct substrate specificity, transporting a wide variety of drugs of diverse therapeutic categories. Studies outlined in the three projects will elucidate the interplay among these three transporters in modulating maternal AND fetal exposure to drugs. Therefore, the three projects will pursue a single goal of elucidating mechanisms by which drug, transporters alter maternal and fetal drug exposure during pregnancy. Results obtained from these studies will have wide-ranging consequences for drug use during pregnancy. First, based on the data we obtain, we will be able to predict which drugs routinely administered to pregnant women are likely to have their disposition affected by pregnancy. Second, our data should allow predictions on the magnitude of change likely to be observed. In a future application, we will test these predictions in the clinic. Once tested, we will be able to predict the magnitude of change in dose that should be instituted for a wide range of drugs whose disposition is significantly modulated by these transporters.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center (P50)
Project #
5P50HD044404-03
Application #
6787314
Study Section
Special Emphasis Panel (ZAR1-AAA-C (O2))
Program Officer
Parrott, Estella C
Project Start
2002-09-26
Project End
2007-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
3
Fiscal Year
2004
Total Cost
$1,099,385
Indirect Cost
Name
University of Washington
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Shuster, Diana L; Bammler, Theo K; Beyer, Richard P et al. (2013) Gestational age-dependent changes in gene expression of metabolic enzymes and transporters in pregnant mice. Drug Metab Dispos 41:332-42
Ke, Alice Ban; Eyal, Sara; Chung, Francisco S et al. (2013) Modeling cyclosporine A inhibition of the distribution of a P-glycoprotein PET ligand, 11C-verapamil, into the maternal brain and fetal liver of the pregnant nonhuman primate: impact of tissue blood flow and site of inhibition. J Nucl Med 54:437-46
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Zhang, Huixia; Wu, Xiaohui; Naraharisetti, Suresh Babu et al. (2009) Pregnancy does not increase CYP3A or P-glycoprotein activity in the non-human primate, Macaca nemestrina. J Pharmacol Exp Ther 330:586-95
Zhang, Yi; Zhou, Lin; Unadkat, Jashvant D et al. (2009) Effect of pregnancy on nitrofurantoin disposition in mice. J Pharm Sci 98:4306-15

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