Pregnant women and their fetuses are therapeutic """"""""orphans."""""""" Drugs are administered to pregnant women, and therefore their fetuses, without the necessary clinical data about the pharmacokinetics, dose, safety, or efficacy of the drugs in these vulnerable populations. To determine the correct dose of a drug to administer to the pregnant woman, it is important to know if the pharmacokinetics of the drug are different in pregnant women when compared with men or non-pregnant women. Many drugs administered to pregnant women are substrates of P-glycoprotein (P-gp) or cytochrome P450 3A enzymes (CYPCA4/5) or both, such as antivirals (e.g., anti-HIV protease inhibitors, antibiotics (e.g., clarithromycin), antihistamines (e.g., fexofenadine), and anti-epileptics (e.g, carbamazepine). P-gp and CYP3A4/5 enzymes are strategically located in the intestine, liver and kidneys?organs important for absorption, metabolism, and excretion of drugs. We have recently obtained evidence from perinatal Phase I clinical trial on indinavir, an anti-HIV protease inhibitor, that the oral clearance of this drug is increased approximately 3-fold during pregnancy. Since the disposition of indinavir is determined by P-gp and CYP3A4/5 enzymes in the intestine and liver, we hypothesized that P-gp and CYP3A4/5 expression and activity in these tissues are enhanced during pregnancy.
The Specific Aims listed below are designed to test this hypothesis. Hypothesis Hepatic and Intestinal P-glycoprotein and CYP3A4/5 expression and activity is enhanced during pregnancy Specific Aims 1. To determine, both antenatal and postpartum, in vivo intestinal and hepatic P-glycoprotein and CYP3A4/5 activities in pregnant women by oral administration of selective substrates of P-gp (digoxin) and CYP3A4/5 (midazolam). 2. To determine, in vivo (or ex vivo), both antenatal and postpartum, intestinal and hepatic P-glycoprotein and CYP3A4/5 activities (or expression) following oral and IV administration of protease inhibitors to a representative animal model, the pregnant M. nemestrina. 3. To determine if activity and expression of P-gp in lymphocytes is elevated during pregnancy in women and M. nemestrina.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center (P50)
Project #
1P50HD044404-01
Application #
6583130
Study Section
Special Emphasis Panel (ZAR1)
Project Start
2002-09-01
Project End
2007-08-31
Budget Start
Budget End
Support Year
1
Fiscal Year
2002
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
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