The overall objective of this grant proposal is to establish an Obstetric-Fetal Pharmacology Unit at the University of Washington. The major goal of the pharmacology unit will be to characterize the pharmacokinetics and pharmacodynamics of drugs that are of therapeutic value during pregnancy and whose clinical pharmacology is altered by the pregnant state. The general research focus will be cytochrome P450 enzymes and membrane transporters. This proposal describes the available environment and resources at the University of Washington for establishing a successful and productive Obstetric-Fetal Pharmacology Research Unit. As a demonstration of our research interests and capabilities the following translational research studies that integrate our strengths in clinical and basic sciences are proposed to evaluate the following study aims. 1.
We aim to determine whether the in vivo activities of CYP2C9 and organic cation transporter (OCT) are altered through stages of pregnancy using the following phenotype markers: glyburide for CYP2C9 and metformin for OCT. Phase I (population pharmacokinetic analysis) and Phase II (pharmacokinetic / pharmacodynamic analysis) studies are proposed to investigate the effects of pregnancy on the aforementioned drug-metabolizing enzymes and transporters (second and third trimesters vs. 3 months postpartum period). 2.
We aim to determine the efficacy and safety of insulin vs. glyburide vs. glyburide plus metformin for treatment of gestational diabetes mellitus. A Phase III efficacy and safety trial is proposed to evaluate the effects of gestational diabetes as well as the treatments on maternal, fetal and infant / child developmental outcomes.

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 #
5U10HD047892-03
Application #
7071650
Study Section
Special Emphasis Panel (ZHD1-DSR-T (17))
Program Officer
Mattison, Donald R
Project Start
2004-07-01
Project End
2009-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
3
Fiscal Year
2006
Total Cost
$600,000
Indirect Cost
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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Caritis, Steve N; Hankins, Gary; Hebert, Mary et al. (2018) Impact of Pregnancy History and 17-Hydroxyprogesterone Caproate on Cervical Cytokines and Matrix Metalloproteinases. Am J Perinatol 35:470-480
Lee, Nora; Hebert, Mary F; Wagner, David J et al. (2018) Organic Cation Transporter 3 Facilitates Fetal Exposure to Metformin during Pregnancy. Mol Pharmacol 94:1125-1131
Kantrowitz-Gordon, Ira; Hays, Karen; Kayode, Olumide et al. (2018) Pharmacokinetics of dacarbazine (DTIC) in pregnancy. Cancer Chemother Pharmacol 81:455-460
Zha, Weibin; Ho, Horace T B; Hu, Tao et al. (2017) Serotonin transporter deficiency drives estrogen-dependent obesity and glucose intolerance. Sci Rep 7:1137
Bergagnini-Kolev, Mackenzie C; Hebert, Mary F; Easterling, Thomas R et al. (2017) Pregnancy Increases the Renal Secretion of N1-methylnicotinamide, an Endogenous Probe for Renal Cation Transporters, in Patients Prescribed Metformin. Drug Metab Dispos 45:325-329
Dorfman, E H; Cheng, E Y; Hebert, M F et al. (2016) Prenatal pharmacogenomics: a promising area for research. Pharmacogenomics J 16:303-4
Costantine, Maged M; Cleary, Kirsten; Hebert, Mary F et al. (2016) Safety and pharmacokinetics of pravastatin used for the prevention of preeclampsia in high-risk pregnant women: a pilot randomized controlled trial. Am J Obstet Gynecol 214:720.e1-720.e17
Lemon, Lara S; Zhang, Hongfei; Hebert, Mary F et al. (2016) Ondansetron Exposure Changes in a Pregnant Woman. Pharmacotherapy 36:e139-41
Sharma, Shringi; Caritis, Steve; Hankins, Gary et al. (2016) Population pharmacokinetics of 17?-hydroxyprogesterone caproate in singleton gestation. Br J Clin Pharmacol 82:1084-93

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