HEPATOTOXICITY OF AN HIV PROTEASE INHIBITOR IN DOGS AND RATS

Oral administration of the HIV protease inhibitor L-689,502 caused cho lestasis and hepatocyte injury in rats and dogs. These changes occurre d rapidly, with elevations in serum transaminase observed as early as 6 hr after oral dosing in dogs. The acute phase of this hepatotoxic re sponse was characterized in more detail in rats. Following intravenous administration, bile flow was decreased in a dose-dependent manner wi th greater than 90% decrease in less than 30 min at a dose of 5 mg/kg. The decrease in bile how was associated with a decrease in erythritol clearance. The decrease in bile flow was not due to disruption of bil iary tight junctions. Sucrose clearance was not increased and biliary bile acid concentrations in treated animals were not different from co ntrols. Unlike control animals, bile flow was not stimulated by infusi on of the bile acid tauroursodeoxycholic acid in animals treated with L-689,502. These cholestatic effects may be due, in part, to direct he patocyte injury. Histological examination of perfusion-fixed livers 30 min after L-689,502 administration revealed periportal changes includ ing hepatocyte vacuolation and occasional single cell necrosis. On a s ubcellular level, the nucleus and mitochondria were intact in less-sev erely affected cells. However, extensive vacuolation with multilamella r inclusions was pronounced in these cells. In addition, canalicular e ctasia was also observed which was consistent with the cholestatic cha nges that were seen. In summary, L-689,502 is a potent, rapid acting h epatotoxin in dogs and rats. The mechanism by which this agent induces cholestasis is novel compared to other well-characterized cholestatic agents such as alpha-naphtylisothiocyanate and ethinyl estradiol. (C) 1997 Academic Press.