Effects of chlorpromazine hydrochloride on bile salt synthesis, bile formation and biliary lipid secretion in the Rhesus monkey: a model for chlorpromazine‐induced cholestasis

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Abstract
Clinical cholestasis associated with the administration of phenothiazine tranquilizers is of particular importance in view of the widespread use of these drugs. The acute effects of i.v. infusions of chlorpromazine hydrochloride on bile salt synthesis, bile formation and biliary lipid secretion were studied in the alert female Rhesus monkey prepared with a total biliary fistula and in a steady bile salt secretory state. In 12 studies (3 animals), 5 doses of radiolabeled chlorpromazine hydrochloride (1-10 mg .ident. 2.8-28 .mu.mol/kg) were infused i.v. for 1 h in random order. Cholestasis was induced within minutes in all experiments. The radiolabel appeared rapidly in bile, with similar recoveries in bile and urine and a 90% total cumulative output in 4 days. Both bile flow, bile salt and other biliary lipid outputs were inhibited in a dose related and reversible manner. The apparent bile salt independent bile flow was consistently abolished, and a prompt return to basal values occurred when biliary concentrations of the drug and metabolites fell below 1-2 mM. When chlorpromazine hydrochloride was infused at 3 doses (2.5, 5.0 and 10.0 mg .ident. 7-28 .mu.mol/kg) during constant i.v infusion of 14C sodium taurocholate (300 .mu.mol/h), bile flow, total bile salt output and 14C taurocholate output decreased within minutes. This was accompanied by a progressive rise in the serum 14C taurocholate concentration. After 90 min the taurocholate specific activity in bile increased significantly indicating that bile salt synthesis was inhibited. Secretion of retained bile salts and reversal of inhibition of bile salt synthesis occurred with time: the course of both events was correlated with the dose of the drug. In monkeys, chlorpromazine hydrochloride apparently induces reversible, dose related cholestasis involving suppression of the bile salt dependent and independent flow, inhibition of bile salt synthesis and impairment of biliary lipid secretion. These effects may be due to both bile salt-chlorpromazine interactions and the effect of the latter on canalicular and other membranes.