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.