Pregnancy Does Not Increase CYP3A or P-Glycoprotein Activity in the Non-Human Primate, Macaca nemestrina

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American Society for Pharmacology and Experimental Therapeutics

RESUMO

Plasma concentrations of protease inhibitors are lower in pregnant women than in nonpregnant women or men. Using nelfinavir as a model protease inhibitor, we have shown that this phenomenon can be reproduced in a representative non-human primate model, Macaca nemestrina (J Pharmacol Exp Ther 329:1016–1022, 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 μg/kg), pregnancy did not affect the oral clearance of the drug administered simultaneously (1 mg/kg p.o.) 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 μg/kg) nor the IA (10 μg/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.

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