SEX-DEPENDENT PHARMACOKINETICS OF INDINAVIR - IN-VIVO AND IN-VITRO EVIDENCE

Indinavir, a potent and specific inhibitor of human immunodeficiency v irus protease, is used for the treatment of AIDS. This study was desig ned to investigate the sex-related differences in kinetics and metabol ism of indinavir in rats, dogs, and monkeys to support the toxicity st udies. When given intravenously, indinavir was cleared rapidly in a po lyphasic manner in all species. Indinavir exhibited significant differ ences in elimination kinetics among species, The rat had the highest p lasma clearance (CL(p); 41-89 ml/min/kg), and the dog had the lowest C L(p) (15-26 ml/min/kg), with the monkey exhibiting an intermediate val ue (36-39 ml/min/kg). Furthermore, marked sex-related differences in C L(p) were observed in rats and dogs, but not in monkeys. The CL(p) was 89 ml/min/kg for male rats and 41 ml/min/kg for female rats. In contr ast to rats, female dogs cleared indinavir more rapidly than male dogs ; the CL(p) was 26 ml/min/kg for female dogs and 15 ml/min/kg far male dogs. Consistent with the in vivo observations, hepatic microsomes fr om male rats had a substantially higher metabolizing activity toward i ndinavir than that from females, whereas liver microsomes from female dogs catalyzed the drug at a higher rate than that from male dogs. Qua litatively, in vitro metabolic profiles of indinavir were similar amon g species and between male and female animals. Studies with an anti-ra t cytochrome P450 (CYP) 3A1 antibody pointed to the probable involveme nt of isoforms in the CYP3A subfamily in the oxidative metabolism of i ndinavir in both males and females of all species. The functional acti vity of CYP3A measured by the formation of testosterone 6 beta-hydroxy lation and immunoblot analysis of the level of CYP3A proteins strongly suggested that gender differences in the levels of CYP3A isoforms may contribute to the observed sex-related differences in indinavir metab olism in rats and dogs.