TICLOPIDINE-INDUCED CHOLESTASIS - REPORT OF 2 CASES AND EXPERIMENTAL-EVIDENCE OF THE DRUGS ADVERSE EFFECT IN ISOLATED-PERFUSED RAT-LIVER

Objective: To investigate the effect of ticlopidine on bile secretion and liver ultrastructure in an attempt to reproduce in vitro ticlopidi ne-induced cholestatic syndrome in humans. Design: Bile flow, bile sal t secretion, enzyme (lactic dehydrogenase, aspartate aminotransferase) release in the perfusate and liver ultrastructure were studied in iso lated perfused rat liver after exposure to ticlopidine. Results: A sin gle pulse of 10 or 30 mg ticlopidine (33 or 99 mumol/l solution) induc ed no significant change in bile flow and bile salt secretion. When th ree consecutive 10 mg pulses of ticlopidien were administered (33 mumo l/l solution perfused for 15-25 min, 40-50 min and 65-75 min; n = 7), the last ticlopidine administration induced a progressive 45% inhibiti on of bile flow associated with a 53% inhibition of bile salt secretio n (P < 0.02 versus controls). Ultrastructural observation of cholestat ic livers showed some features of intrahepatic cholestasis with numero us electron dense bile bodies and granules in the hepatocyte cytoplasm , but without necrosis or significant damage of intracellular organell es. The bile canaliculus appeared to be almost normal. Conclusions: Re peated acute administration of ticlopidine promotes marked cholestasis in isolated perfused rat liver, reproducing the adverse effect of the drug in humans. These findings show that cholestasis may be caused di rectly by ticlopidine or by its hepatic metabolites rather than by a d rug hypersensitivity.