Effects of three H2 antagonists on the isolated perfused rat liver. Correlation of bile flow changes with potential for causing hepatic disease in patients.
The adverse effects of oxmetidine, an H2 blocking agent which has been shown to produce hepatic injury in 1-4% of patients, on an in vitro model were compared with those of cimetidine and ranitidine which have led to only rare instances of hepatic injury. Bile flow was measured in the isolated perfused rat liver (Wistar rats), comparing the effects of each of the three drugs with control perfusions. Oxmetidine in concentrations of 3 X 10(-3) M or greater led to a decrease in bile flow within 15 min and, at a concentration of 5 X 10(-3) M, to complete cessation of flow within 5 min. Lower concentrations (5 X 10(-4) M) led to a marked choleresis. Ranitidine and cimetidine in concentrations up to 5 X 10(-3) M produced no decrease in bile flow. Ranitidine, however, led to a choleresis at a concentration of 5 X 10(-3) M. 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.
D000818:Animals; D001646:Bile / Q000187:drug effects / Q000502:physiology*; D056486:Chemical and Drug Induced Liver Injury; D002927:Cimetidine / Q000494:pharmacology / Q000633:toxicity*; D007093:Imidazoles / Q000494:pharmacology / Q000633:toxicity*; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000187:drug effects; D008297:Male; D010477:Perfusion; D011899:Ranitidine / Q000494:pharmacology / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains
D007093:Imidazoles; D002927:Cimetidine; D011899:Ranitidine; C027703:oxmetidine