As in humans, pregnancy increases the clearance of the protease inhibitor, nelfinavir, in the non-human primate, M. nemestrina. The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] Journal article | | Title | As in humans, pregnancy increases the clearance of the protease inhibitor, nelfinavir, in the non-human primate, M. nemestrina. | | Author(s) | Zhang H, Wu X, Chung F, Naraharisetti SB, Whittington D, Mirfazaelian A, Unadkat JD | | Institution | Department of Pharmaceutics, University of Washington. | | Source | J Pharmacol Exp Ther 2009 Mar 17. | | Abstract | The apparent oral clearance of protease inhibitors (PIs) is increased in pregnant women. Though this phenomenon is reproduced in the mouse, because of the multiplicity of mouse CYP 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 non-human primate, we first determined if this phenomenon could be reproduced in M. nemestrina, using nelfinavir as a model PI. Consistent with the human and mouse studies, we found that the apparent oral clearance of 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 (~ 45 %) during pregnancy. In vitro, pregnancy significantly enhanced the rate of NFV depletion in hepatic S-9 fractions, but not in 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 concluded 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. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19293388 |
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