Effects of H2-Blocking Agents on Hepatocytes in Vitro: Correlation with Potential for Causing Hepatic Disease in Patients

Abstract

The adverse effects on an in vitro model of oxmetidine, an H2-blocking agent which has been shown to produce hepatic injury in 1 to 4% of patients, were compared with those of cimetidine and ranitidine which have led to only rare instances of hepatic injury. Suspensions of hepatocytes, freshly isolated from Sprague-Dawley rats, were exposed to the three drugs. Oxmetidine, in concentrations of 3 X lop3 M or greater, led to leakage of AST into the medium after 4 hr of incubation. Ranitidine and cimetidine, in concentrations up to 5 X loT3 M, produced no identifiabile leakage. Pretreatment of rats with phenobarbital, 3-methylcholanthrene, or SKF 525A resulted in no significant enhancement or inhibition of the oxmetidine effects. These results suggest that the adverse effects of oxmetidine on the hepatocytes are produced by the native compound, not a metabolite. The positive correlation between in vivo and in vitro toxicity supports the view that in vitro testing may prove to be of use in predicting the hepatotoxic potential of a drug.

Ranitidine Treatment during a Modest Inflammatory Response Precipitates Idiosyncrasy-Like Liver Injury in Rats

“…Interestingly, RAN attenuates liver injury after ischemia-reperfusion, probably by inhibiting release of cytotoxic factors by PMNs (Okajima et al, 2002). Previous studies demonstrated that RAN was nontoxic to hepatocytes even at high (e.g., 5 mM) concentrations (Zimmerman et al, 1986), and our results confirmed these findings (Fig. 5).…”