Search

Oral administration of the HIV protease inhibitor L-689,502 caused cholestasis and hepatocyte injury in rats and dogs. These changes occurred rapidly, with elevations in serum transaminase observed as early as 6 hr after oral dosing in dogs. The acute phase of this hepatotoxic response was characterized in more detail in rats. Following intravenous administration, bile flow was decreased in a dose-dependent manner with greater than 90% decrease in less than 30 min at a dose of 5 mg/kg. The decrease in bile flow was associated with a decrease in erythritol clearance. The decrease in bile flow was not due to disruption of biliary tight junctions. Sucrose clearance was not increased and biliary bile acid concentrations in treated animals were not different from controls. Unlike control animals, bile flow was not stimulated by infusion of the bile acid tauroursodeoxycholic acid in animals treated with L-689,502. These cholestatic effects may be due, in part, to direct hepatocyte injury. Histological examination of perfusion-fixed livers 30 min after L-689,502 administration revealed periportal changes including hepatocyte vacuolation and occasional single cell necrosis. On a subcellular level, the nucleus and mitochondria were intact in less-severely affected cells. However, extensive vacuolation with multilamellar inclusions was pronounced in these cells. In addition, canalicular ectasia was also observed which was consistent with the cholestatic changes that were seen. In summary, L-689,502 is a potent, rapid acting hepatotoxin 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., (Copyright 1997 Academic Press.)

The effects of a racemic leukotriene antagonist (MK-0571) and its component enantiomers (L-668,018 and L-668,019) on hepatic peroxisome proliferation were examined in mice, rats, and rhesus monkeys. Administration of racemic MK-0571 to mice resulted in increased liver weights, increased peroxisomal volume density, and a pleiotropic induction of characteristic peroxisomal and nonperoxisomal enzyme activities associated with peroxisomal proliferation. When the individual enantiomers of MK-0571 were administered to mice, a pronounced enantioselective induction of peroxisome proliferation was observed. Toxicokinetic studies showed that the levels of each enantiomer in the liver or plasma after separate administration were similar. Thus, the enantioselectivity in the induction of peroxisome proliferation could not be explained on the basis of pharmacokinetic differences between the enantiomers. The hepatic peroxisomal response of the rat to MK-0571 was greatly attenuated compared to the mouse. As has been seen with other peroxisome-proliferating agents, MK-0571 had no effect on either peroxisomal volume density or peroxisomal enzyme activity in monkeys. Due to the high degree of enantiomeric discrimination toward the induction of peroxisomal proliferation by these enantiomers, compounds of this type may prove useful as probes to examine the mechanisms by which peroxisomal proliferating agents induce their effects.

Differences in the nature and extent of hepatic injury were examined after administration of para-substituted thiobenzamides to rats. In accordance with previous studies, the extent of hepatotoxicity varied with the electron-donating ability of the substituent. There was also a good correlation between the extent of hepatic necrosis and the amount of substituted thiobenzamide sulfoxide found in the plasma after intraperitoneal dosing. The nature of the hepatic lesion, characterized as a combination of hepatic necrosis, ballooning degeneration, and biliary dysfunction, varied qualitatively with each thiobenzamide analog. When the hepatotoxicity of thiobenzamide was compared after either intraperitoneal or oral dosing, differences in the extent of hepatic necrosis, ballooning degeneration, transaminase elevation, and biliary dysfunction were observed. Intraperitoneal dosing with thiobenzamide gave less severe necrosis and more pronounced elevations in bile acids, while oral dosing led to more severe necrosis along with impaired biliary function. The route of administration was shown to dramatically affect the pharmacokinetics of thiobenzamide and thiobenzamide sulfoxide. Intraperitoneal administration of thiobenzamide gave high plasma and liver levels of both thiobenzamide and thiobenzamide sulfoxide, whereas oral administration gave slightly lower levels of the sulfoxide but much lower levels of thiobenzamide. The reason for greater hepatic necrosis after oral administration may be due to a greater ability to further metabolize the sulfoxide to a reactive metabolite in the absence of high levels of thiobenzamide.