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

Abstract

We studied the acute effects of intravenous infusions of chlorpromazine hydrochloride on bile salt synthesis, bile formation and biliary lipid secretion in the alert female Rhesus monkey prepared with a total biliary fistula and in a steady bile salt secretory state. In twelve studies (three animals), five doses of radiolabelled chlorpromazine hydrochloride (1-10 mg identical to 2.8-28 mumol/kg) were infused intravenously 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 concentration of the drug and metabolities fell below 1-2 mM. When chlorpromazine hydrochloride was infused at three doses (2.5, 5.0 and 10.0 mg identical to 7-28 mumol/kg) during constant intravenous infusion of 14C sodium taurocholate (300 mumol/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. Thus, in monkeys, chlorpromazine hydrochloride induces reversible, dose related cholestasis suppression of the bile salt dependent and independent flow, inhibition of bile salt synthesis and impairment of biliary lipid secretion. We suggest that these effects are due to both bile salt-chlorpromazine interactions and the effect of the latter on canalicular and other membranes.