Abstract

Indinavir, a potent and specific inhibitor of human immunodeficiency virus protease, is undergoing clinical investigation for the treatment of acquired immunodeficiency syndrome. The studies described herein were designed to characterize the absorption, distribution, metabolism, and excretion of the drug in rats, dogs, and monkeys. Indinavir exhibited marked species differences in elimination kinetics. The plasma clearance was in the rank order: rat (107 ml/min/kg) > monkey (36 ml/min/kg) > dog (16 ml/min/kg). Significant differences in the bioavailability of indinavir also were observed. When given orally as a solution in 0.05 M citric acid, the bioavailability varied significantly from 72% in the dog to 19% in the monkey, and 24% in the rat. These differences in bioavailability were attributed mainly to species differences in the magnitude of hepatic first-pass metabolism. The distribution of indinavir was studied only in rats, both intravenously and orally. Intravenously, indinavir was distributed widely throughout the body. Brain uptake studies showed that indinavir penetrated the blood-brain barrier, but that the penetration was limited. After oral administration, indinavir was distributed rapidly into and out of the lymphatic system. The rapid lymph transfer is of clinical relevance, because a primary clinical hallmark of acquired immunodeficiency syndrome is the depletion of CD4 lymphocytes. Biliary and urinary recovery studies revealed that metabolism was the major route of indinavir elimination in all species, and N-dealkylation, N-oxidation, and hydroxylation seemed to be the major pathways. Although limited to qualitative aspects, the metabolite profile obtained from in vitro microsomal studies generally reflected the in vivo oxidative metabolism of indinavir in all species studies. Results from the chemical and immunochemical inhibition studies indicated the possible involvement of isoforms of the CYP3A subfamily in the oxidative metabolism of indinavir in rats, dogs, and monkeys. This is consistent with our previous studies, which have shown that CYP3A4 is the isoform responsible for the oxidative metabolism of indinavir in human liver microsomes. Furthermore, the in vivo oxidative metabolism of indinavir in rats, dogs, and monkeys was qualitatively similar to that in humans. The high degree of similarity in the metabolite profiles of drug metabolism between animals and humans validates the use of these animal models for toxicity studies of indinavir. Attempts were made to quantitatively extrapolate in vitro metabolic data to in vivo metabolism. With the application of the well-stirred and parallel-tube models, the hepatic clearance and hepatic extraction ratio were calculated using the in vitro Vmax/Km values. In rats, the predicted hepatic clearance (31 ml/ min/kg) and hepatic extraction ratio (0.47) agreed well with the observed in vivo hepatic clearance (43 ml/min/kg) and hepatic extraction ratio (0.68). In addition, the hepatic clearance of indinavir was predicted reasonably well in dogs and monkeys. Based on the in vitro intrinsic clearance of human liver microsomes, a small but significant hepatic first-pass metabolism (ca. 25%) is expected in humans.