SPECIES-DIFFERENCES IN THE PHARMACOKINETICS AND METABOLISM OF INDINAVIR, A POTENT HUMAN-IMMUNODEFICIENCY-VIRUS PROTEASE INHIBITOR

Indinavir, a potent and specific inhibitor of human immunodeficiency v irus protease, is undergoing clinical investigation for the treatment of acquired immunodeficiency syndrome. The studies described herein we re designed to characterize the absorption, distribution, metabolism, and excretion of the drug in rats, dogs, and monkeys. Indinavir exhibi ted marked species differences in elimination kinetics. The plasma cle arance was in the rank order: rat (107 ml/min/kg) > monkey (36 ml/min/ kg) > dog (16 ml/min/kg). Significant differences in the bioavailabili ty 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 difference s in bioavailability were attributed mainly to species differences in the magnitude of hepatic first-pass metabolism. The distribution of in dinavir was studied only in rats, both intravenously and orally. Intra venously, indinavir was distributed widely throughout the body. Brain uptake studies showed that indinavir penetrated the blood-brain barrie r, but that the penetration was limited. After oral administration, in dinavir was distributed rapidly into and out of the lymphatic system. The rapid lymph transfer is of clinical relevance, because a primary c linical hallmark of acquired immunodeficiency syndrome is the depletio n of CD4 lymphocytes. Biliary and urinary recovery studies revealed th at metabolism was the major route of indinavir elimination in all spec ies, and N-dealkylation, N-oxidation, and hydroxylation seemed to be t he major pathways. Although limited to qualitative aspects, the metabo lite profile obtained from in vitro microsomal studies generally refle cted the in vivo oxidative metabolism of indinavir in all species stud ied, Results from the chemical and immunochemical inhibition studies i ndicated the possible involvement of isoforms of the CYP3A subfamily i n the oxidative metabolism of indinavir in rats, dogs, and monkeys. Th is is consistent with our previous studies, which have shown that CYP3 A4 is the isoform responsible for the oxidative metabolism of indinavi r in human liver microsomes, Furthermore, the in vivo oxidative metabo lism of indinavir in rats, dogs, and monkeys was qualitatively similar to that in humans. The high degree of similarity in the metabolite pr ofiles of drug metabolism between animals and humans validates the use of these animal models for toxicity studies of indinavir. Attempts we re made to quantitatively extrapolate in vitro metabolic data to in vi vo metabolism. With the application of the well-stirred and parallel-t ube models, the hepatic clearance and hepatic extraction ratio were ca lculated using the in vitro V-max/K-m values. In rats, the predicted h epatic clearance (31 ml/min/kg) and hepatic extraction ratio (0.47) ag reed well with the observed in vivo hepatic clearance (43 ml/min/kg) a nd 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 smal l but significant hepatic first-pass metabolism (ca. 25%) is expected in humans.