The overall objective of this grant proposal is to obtain continued funding for the University of Washington Obstetric-fetal Pharmacology Research Unit (UW OPRU). Pregnant women undergo extensive physiological and biochemical changes not experienced by non-pregnant patients, making them unique with respect to drug therapy selection, dosage, efficacy and safety. Medication use during pregnancy potentially results in fetal exposure and toxicity. On average, women ingest three different drugs during pregnancy;about 66% of these have never been tested in pregnant women. They are administered without the necessary clinical data on the pharmacokinetics, dose, safety, or efficacy during pregnancy. Without such data, the FDA would never approve a drug for the adult non-pregnant population. The impact of insufficient information has translated into either unproven empiric therapy for pregnant women or withholding of critical therapy from women with medically complicated pregnancies. The major goal of the UW OPRU is to identify study and characterize drugs that are of therapeutic value during pregnancy and whose disposition and response are altered by the pregnant state in normal or abnormal pregnancies. The UW OPRU will conduct multidisciplinary, basic, translational and clinical research studies in order to improve care for pregnant women, their fetuses and neonates. The proposed research plan focuses primarily on the gestational age dependent changes in the pharmacokinetics and pharmacodynamics of oral anti-diabetic agents (glyburide and metformin) in the treatment of gestational diabetes mellitus (GDM) and has been developed based upon the following overarching Specific Aims:
Specific Aim 1. Clinical study: To evaluate at 3 stages of treatment (prior to, during initial treatment and after achieving glycemic control) the effects of pregnancy on the PK/PD of glyburide and metformin.
Specific Aim 2. Basic Science and Translational studies: To characterize the time course of and elucidate the biological mechanisms underlying pregnancy-induced changes in drug transporters and drug metabolizing enzymes.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Cooperative Clinical Research--Cooperative Agreements (U10)
Project #
5U10HD047892-08
Application #
8206489
Study Section
Special Emphasis Panel (ZHD1-DSR-Z (02))
Program Officer
Ren, Zhaoxia
Project Start
2004-07-01
Project End
2014-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
8
Fiscal Year
2012
Total Cost
$792,100
Indirect Cost
$276,550
Name
University of Washington
Department
Other Health Professions
Type
Schools of Pharmacy
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Isoherranen, Nina; Thummel, Kenneth E (2013) Drug metabolism and transport during pregnancy: how does drug disposition change during pregnancy and what are the mechanisms that cause such changes? Drug Metab Dispos 41:256-62
Haas, David M; Quinney, Sara K; Clay, Jayanti M et al. (2013) Nifedipine pharmacokinetics are influenced by CYP3A5 genotype when used as a preterm labor tocolytic. Am J Perinatol 30:275-81
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
Lee, Nora; Hebert, Mary F; Prasad, Bhagwat et al. (2013) Effect of gestational age on mRNA and protein expression of polyspecific organic cation transporters during pregnancy. Drug Metab Dispos 41:2225-32
Ke, Alice Ban; Nallani, Srikanth C; Zhao, Ping et al. (2013) A physiologically based pharmacokinetic model to predict disposition of CYP2D6 and CYP1A2 metabolized drugs in pregnant women. Drug Metab Dispos 41:801-13

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