Pregnancy does not increase CYP3A or P-glycoprotein activity in the non-human primate, Macaca nemestrina.
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.
Zhang
Huixia
H
Department of Pharmaceutics, University of Washington, Seattle, Washington 98195, USA.
Wu
Xiaohui
X
Naraharisetti
Suresh Babu
SB
Chung
Francisco
F
Whittington
Dale
D
Mirfazaelian
Ahmad
A
Unadkat
Jashvant D
JD
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000097:blood*; D000818:Animals; D000831:Animals, Newborn; D051544:Cytochrome P-450 CYP3A / Q000097:blood*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005260:Female; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000097:blood; D008254:Macaca nemestrina / Q000097:blood*; D008874:Midazolam / Q000008:administration & dosage / Q000097:blood; D019888:Nelfinavir / Q000008:administration & dosage / Q000097:blood; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000097:blood*; D011270:Pregnancy, Animal / Q000097:blood* / Q000187:drug effects
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017320:HIV Protease Inhibitors; D011257:Pregnancy Proteins; D051544:Cytochrome P-450 CYP3A; D019888:Nelfinavir; D008874:Midazolam