This proposal describes the Obstetrical-Fetal Pharmacology Research Unit (OPRU) at the University of Pittsburgh. The Pittsburgh OPRU has been highly successful in its original objectives and has contributed to the Network of OPRUs substantially. We have participated in concept proposals, protocol development, recruitment, data analysis and data sharing. The Pittsburgh OPRU has focused its research on the study of 17-hydroxyprogesterone caproate, the only agent at the time shown to reduce the risk of preterm birth in women with a prior preterm birth. We have defined the pharmacology of this agent and have presented our data at national meetings on behalf of the OPRU. In this application, we propose to study the pharmacology of vaginal progestins used in pregnant women with a short cervix. A recent call from the American College of Obstetrics and Gynecology encouraged research to define the proper dosing and formulation for progestin use in pregnancy. We will recruit women between 16 and 22 weeks gestation whose cervix is <30 mm in length. These women are at high risk for preterm birth. We will obtain cervicovaginal fluid prior to treatment and again weekly for 4 weeks after treatment with one of the two progestational agents (Prochieve and Prometrium) with apparent clinical benefit. We will evaluate the pharmacokinetics (PK) of these two agents as well as the pharmacodynamic impact of these agents on cervicovaginal fluid biomarkers including cervical length and density, matrix metalloproteinases, cytokines, and the cervicovaginal proteome. These analyses will allow us to compare the PK of these two progestins, identify their targets and evaluate whether these treatments alter cervical structure. Our second study will evaluate the impact of polymorphisms of drug metabolizing enzymes and pregnancy hormones on the activity of the two major drug metabolizing enzymes CYP, 2C9 and 2D6. We will screen 200 pregnant women and identify those with P450 enzyme polymorphisms known to affect enzyme activity. These polymorphisms commonly lead to a highly variable in enzyme activity. We will administer to these women a cocktail composed of indomethacin and dextromethorphan to evaluate the activity of the cytochrome P450 enzymes once during pregnancy and once postpartum. We will obtain hepatocytes which also express the polymorphisms of interest in CYP, 2C9 and 2D6 and challenge them with estrogen and progesterone to determine the hormone's effects. Finally, we will evaluate the fetal contribution to the variability in activity of these three CYP enzymes by evaluating cord/placental CYP enzymes/polymorphisms.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Cooperative Clinical Research--Cooperative Agreements (U10)
Project #
Application #
Study Section
Special Emphasis Panel (ZHD1-DSR-Z (02))
Program Officer
Ren, Zhaoxia
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Magee-Women's Research Institute and Foundation
United States
Zip Code
Caritis, Steve N; Venkataramanan, Raman; Thom, Elizabeth et al. (2014) Relationship between 17-alpha hydroxyprogesterone caproate concentration and spontaneous preterm birth. Am J Obstet Gynecol 210:128.e1-6
Grobman, William A; Bailit, Jennifer L; Rice, Madeline Murguia et al. (2014) Frequency of and factors associated with severe maternal morbidity. Obstet Gynecol 123:804-10
Feghali, Maisa; Venkataramanan, Raman; Caritis, Steve (2014) Prevention of preterm delivery with 17-hydroxyprogesterone caproate: pharmacologic considerations. Semin Perinatol 38:516-22
Chang, Justine; Zhao, Yang; Zhao, Wenchen et al. (2014) Quality assessment of compounded 17-hydroxyprogesterone caproate. Am J Obstet Gynecol 210:47.e1-7
Zhao, Yang; Alshabi, Ali Mohamed; Caritis, Steve et al. (2014) Impact of 17-alpha-hydroxyprogesterone caproate on cytochrome P450s in primary cultures of human hepatocytes. Am J Obstet Gynecol 211:412.e1-6
Pillai, Venkateswaran C; Strom, Stephen C; Caritis, Steve N et al. (2013) A sensitive and specific CYP cocktail assay for the simultaneous assessment of human cytochrome P450 activities in primary cultures of human hepatocytes using LC-MS/MS. J Pharm Biomed Anal 74:126-32
Caritis, Steve N; Zhao, Yang; Bettinger, Joseph et al. (2013) Qualitative and quantitative measures of various compounded formulations of 17-alpha hydroxyprogesterone caproate. Am J Obstet Gynecol 208:470.e1-5
Sharma, Shringi; Ellis, Ewa C S; Gramignoli, Roberto et al. (2013) Hepatobiliary disposition of 17-OHPC and taurocholate in fetal human hepatocytes: a comparison with adult human hepatocytes. Drug Metab Dispos 41:296-304
Cuppett, Courtney D; Zhao, Yang; Caritis, Steve et al. (2013) Effect of endogenous steroid hormones on 17-alpha-hydroxyprogesterone caproate metabolism. Am J Obstet Gynecol 208:86.e1-6
Caritis, Steve N; Hebert, Mary F (2013) A pharmacologic approach to the use of glyburide in pregnancy. Obstet Gynecol 121:1309-12

Showing the most recent 10 out of 19 publications