The species-dependent metabolism of efavirenz produces a nephrotoxic glutathione conjugate in rats

Efavirenz, a potent nonnucleoside reverse transcriptase inhibitor widely pr escribed for the treatment of HIV infection, produces renal tubular epithel ial cell necrosis in rats but not in cynomolgus monkeys or humans. This spe cies selectivity in nephrotoxicity could result from differences in the pro duction or processing of reactive metabolites, or both. A detailed comparis on of the metabolites produced by rats, monkeys, and humans revealed that r ats produce a unique glutathione adduct. The mechanism of formation and rol e of this glutathione adduct in the renal toxicity were investigated using both chemical and biochemical probes. Efavirenz was labeled at the methine position on the cyclopropyl ring with the stable isotope deuterium, effecti vely reducing the formation of the cyclopropanol metabolite, an obligate pr ecursor to the glutathione adduct. This substitution markedly reduced both the incidence and severity of nephrotoxicity as measured histologically. Fu rther processing of this glutathione adduct was also important in producing the lesion and was demonstrated by inhibiting gamma -glutamylranspeptidase with acivicin pretreatment (10 mg;kg, IV) prior to dosing with efavirenz. Again, both the incidence and severity of the nephrotoxicity were reduced, such that four of nine rats given acivicin were without detectable lesions. These studies provide compelling evidence that a species-specific formatio n of glutathione conjugate(s) from efavirenz is involved in producing nephr otoxicity in rats. Mechanisms are proposed for the formation of reactive me tabolites that could be responsible for the renal toxicity observed in rats . (C) 2000 Academic Press.