UWSCOR Project 1:
Changes in Hepatic and Intestinal P-glycoprotein and CYP3A Activity During Pregnancy.
PI: Jashvant Unadkat, Ph.D.
- Co-Investigators: Thomas Easterling, MD; Mary Hebert, Pharm D; Kenneth Thummel, PhD
Many drugs administered to pregnant women are transported by P-glycoprotein (P-gp) or metabolized by cytochrome P450 3A enzymes (CYP3A4/5) or both, such as antivirals (e.g., anti-HIV protease inhibitors), antibiotics (e.g., clarithromycin), antihistamines (e.g., fexofenadine) and antiepileptics (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 a perinatal Phase I clinical trial on indinavir, an anti-HIV protease inhibitor, that the concentrations of this drug achieved in the blood plasma of pregnant women is decreased by ~3-fold during pregnancy. Since the disposition of indinavir is determined by P-gp transport and CYP3A4/5 metabolism in the intestine and liver, we have hypothesized that:
Hepatic and Intestinal P-glycoprotein and Cyp3A4/5 expression and activity is enhanced during pregnancy.
Aims:
- 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).
- 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.
- To determine if activity and expression of P-gp in lymphocytes is elevated during pregnancy in women and M. nemestrina.
Once these studies have been completed:
- We will be able to predict which of the many drugs administered to pregnant women will also have their pharmacokinetics affected
- We may be able to predict how the doses of these drugs should be adjusted during pregnancy to maintain efficacy.