Ticlopidine-induced cholestasis

Objective: To investigate the effect of ticlopidine on bile secretion and liver ultrastructure in an attempt to reproduce in vitro ticlopidine-induced cholestatic syndrome in humans. Design: Bile flow, bile salt secretion, enzyme (lactic dehydrogenase, aspartate aminotransferase) release in the perfusate and liver ultrastructure were studied in isolated perfused rat liver after exposure to ticlopidine. Results: A single pulse of 10 or 30 mg ticlopidine (33 or 99[mu]mol/l solution) induced no significant change in bile flow and bile salt secretion. When three consecutive 10 mg pulses of ticlopidine were administered (33[mu]mol/l solution perfused for 15-25 min, 40-50 min and 65-75 min; n = 7), the last ticlopidine administration induced a progressive 45% inhibition of bile flow associated with a 53% inhibition of bile salt secretion (P<0.02 versus controls). Ultrastructural observation of cholestatic livers showed some features of intrahepatic cholestasis with numerous electron dense bile bodies and granules in the hepatocyte cytoplasm, but without necrosis or significant damage of intracellular organelles. The bile canaliculus appeared to be almost normal. Conclusions: Repeated 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 directly by ticlopidine or by its hepatic metabolites rather than by a drug hypersensitivity.