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Pregnancy does not increase CYP3A or P-glycoprotein activity in the non-human primate, Macaca nemestrina.
- Source :
-
The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2009 Aug; Vol. 330 (2), pp. 586-95. Date of Electronic Publication: 2009 May 28. - Publication Year :
- 2009
-
Abstract
- 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 ( approximately 70%) during pregnancy after intra-arterial (IA) administration of the drug ((15)N-labeled MDZ; 40 microg/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 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.
- Subjects :
- Animals
Animals, Newborn
Enzyme Activation drug effects
Enzyme Activation physiology
Female
HIV Protease Inhibitors administration & dosage
HIV Protease Inhibitors blood
Midazolam administration & dosage
Midazolam blood
Nelfinavir administration & dosage
Nelfinavir blood
Pregnancy
Pregnancy, Animal drug effects
ATP Binding Cassette Transporter, Subfamily B, Member 1 blood
Cytochrome P-450 CYP3A blood
Macaca nemestrina blood
Pregnancy Proteins blood
Pregnancy, Animal blood
Subjects
Details
- Language :
- English
- ISSN :
- 1521-0103
- Volume :
- 330
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- The Journal of pharmacology and experimental therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 19478134
- Full Text :
- https://doi.org/10.1124/jpet.109.153569