Pregnancy does not increase CYP3A or P-glycoprotein activity in the non-human primate, Macaca. nemestrina. The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] Journal article | | Title | Pregnancy does not increase CYP3A or P-glycoprotein activity in the non-human primate, Macaca. nemestrina. | | Author(s) | Zhang H, Wu X, Naraharisetti SB, Chung F, Whittington D, Mirfazaelian A, Unadkat JD | | Institution | Department of Pharmaceutics, University of Washington. | | Source | J Pharmacol Exp Ther 2009 May 28. | | Abstract | Plasma concentrations of protease inhibitors (PIs) are lower in pregnant women than in non-pregnant women or men. Using nelfinavir as a model PI, we have shown that this phenomenon can be reproduced in a representative non-human primate model, M. nemestrina (Zhang et al., 2009). Nelfinavir is cleared from the body predominantly by CYP3A metabolism and P-glycoprotein (P-gp) efflux. Therefore, using midazolam (MDZ) as a CYP3A probe, and digoxin (DIG) as a P-gp probe, we determined the antepartum (73-118 days) and postpartum (61-130 days) in vivo intestinal and hepatic CYP3A or P-gp activity in the macaque. Although the systemic clearance of MDZ was significantly increased (~ 70 %) during pregnancy after intra-arterial (IA) administration of the drug (15N-labeled MDZ; 40 microg/kg), pregnancy did not affect the oral clearance of the drug administered simultaneously (1 mg/kg, PO) with the IA dose. In vitro studies in hepatic and intestinal S-9 fractions indicated no effect of pregnancy on CYP3A activity or protein expression in the small intestine or liver. In contrast, neither the oral (100 microg /kg) nor the IA (10 microg/kg) clearance of DIG was significantly altered by pregnancy, indicating no effect of pregnancy on P-gp activity. Assuming that MDZ and DIG are selective substrates of the macaque CYP3A enzymes and P-gp respectively, these results suggest that factors other than increased CYP3A or P-gp activity contribute to the increased clearance of protease inhibitors during M. nemestrina pregnancy. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19478134 |
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