As in humans, pregnancy increases the clearance of the protease inhibitor nelfinavir in the nonhuman primate Macaca nemestrina.
The apparent oral clearance of protease inhibitors (PIs) is increased in pregnant women. Although this phenomenon is reproduced in the mouse, because of the multiplicity of mouse cytochrome P450 isoforms, lack of information on their substrate and inhibitor selectivity, and lack of reagents (e.g., antibodies, purified protein), it is difficult to study the mechanistic basis of this phenomenon in this animal model. To investigate the mechanistic basis of this phenomenon in a more representative model, the nonhuman primate, we first determined whether this phenomenon could be reproduced in Macaca nemestrina, using nelfinavir as a model PI. Consistent with the human and mouse studies, we found that the apparent oral clearance of nelfinavir (NFV) in the macaques was significantly increased (3.14-fold) antepartum (n = 3) versus postpartum (n = 4). This increased apparent oral clearance was a result of an increased systemic clearance (1.9-fold) and a decreased bioavailability (approximately 45%) during pregnancy. In vitro, pregnancy significantly enhanced the rate of NFV depletion in hepatic, but not intestinal S-9 fractions. Human CYP3A inhibitors erythromycin (0.5 mM), ketoconazole (0.5 microM), and troleandomycin (0.01-1 mM), but not the CYP2C inhibitor, sulfaphenazole (3 microM), significantly inhibited the depletion of NFV in hepatic S-9 fractions and expressed rhesus CYP3A64 enzyme. Based on these data, we conclude that increased hepatic activity of NFV-metabolizing enzymes (perhaps CYP3A enzymes) results in increased clearance of PIs during pregnancy in the macaques. The M. nemestrina should be further investigated as a model to study the mechanisms by which the clearance of PIs is increased during pregnancy.
Zhang
Huixia
H
Department of Pharmaceutics, University of Washington, Box 357610, Seattle, WA 98195, USA.
Wu
Xiaohui
X
Chung
Francisco
F
Naraharisetti
Suresh Babu
SB
Whittington
Dale
D
Mirfazaelian
Ahmad
A
Unadkat
Jashvant D
JD
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D017320:HIV Protease Inhibitors / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D007269:Injections, Intra-Arterial; D007421:Intestine, Small / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008254:Macaca nemestrina; D009249:NADP / Q000378:metabolism; D019888:Nelfinavir / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D011247:Pregnancy / Q000378:metabolism*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism
D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D017320:HIV Protease Inhibitors; D011994:Recombinant Proteins; D009249:NADP; D051544:Cytochrome P-450 CYP3A; D019888:Nelfinavir