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.
| Ryu, Rachel J; Easterling, Thomas R; Caritis, Steve N et al. (2018) Prednisone Pharmacokinetics During Pregnancy and Lactation. J Clin Pharmacol 58:1223-1232 |
| 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 |
| 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 |
| Ryu, Rachel J; Eyal, Sara; Easterling, Thomas R et al. (2016) Pharmacokinetics of metoprolol during pregnancy and lactation. J Clin Pharmacol 56:581-9 |
| Dorfman, E H; Cheng, E Y; Hebert, M F et al. (2016) Prenatal pharmacogenomics: a promising area for research. Pharmacogenomics J 16:303-4 |
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