Preterm birth (PTB), birth prior to 37 weeks of gestational age, is a major cause of early childhood mortality and morbidity in the United States. 17alpha-hydroxyprogesterone caproate (17-OHPC) has recently been documented to reduce the incidence of preterm birth. A complete understanding of the pharmacokinetics of 17-OHPC will help in improving clinical outcome.
The goal of this dissertation research was to evaluate the preclinical and clinical pharmacology of 17-OHPC in order to optimize the use of this drug in preventing preterm birth.
Studies in human liver microsomes and human hepatocytes indicate that 17-OHPC is metabolized by CYP3A. Significant transplacental transfer of 17-OHPC (cord blood to maternal plasma ratio of 0.3) has been observed in pregnant subjects. Studies were performed in fetal hepatocytes to evaluate the metabolism of 17-OHPC. Fetal hepatocytes demonstrate the ability of human fetal liver to metabolize 17-OHPC to fetal specific metabolites, with oxidation being the major metabolic pathway. Further, 17-OHPC and/or its metabolites inhibit bile salt transport in both adult and fetal hepatocytes.
To understand the clinical pharmacology of 17-OHPC, pregnant women who received 17-OHPC for clinical reasons were studied and blood samples collected periodically. Wide-interindividual variation was observed in the pharmacokinetics of 17-OHPC in pregnant subjects. The half life of 17-OHPC was 9 days and plasma concentrations of 17-OHPC did not achieve steady state. The race and body mass index of the pregnant subjects affect the plasma levels of 17-OHPC.
In conclusion, since CYP3A is involved in the oxidative metabolism of numerous commonly used drugs; 17-OHPC may be involved in clinically relevant metabolic drug interactions with co-administered CYP3A inhibitors or inducers. Since 17-OHPC crosses the placental barrier and reaches the fetus, use of higher doses of 17-OHPC should be approached with caution. The clinical effectiveness of 17-OHPC in preventing preterm birth has been observed in only 33% of the patients. Given the wide interindividual variability, modification of the starting dose based on BMI and race alongwith monitoring of plasma levels and adjustment of subsequent doses accordingly may be needed to improve therapeutic outcomes in the treatment of preterm birth with 17-OHPC.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-04282010-030454 |
| Date | 11 May 2010 |
| Creators | Sharma, Shringi |
| Contributors | Stephen C. Strom, Wen Xie, Raman Venkataramanan, Steve N. Caritis, Samuel M. Poloyac, Billy W. Day |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-04282010-030454/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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