5, 0-4000 Dusseldorf, Federal Republic of Germany Chlorpromazine (10 pmol/L) causes a marked increase in portal pressure in perfused rat liver. Simultaneously, oxygen consumption, hepatic clearance of taurocholate and bile flow are diminished. These effects are prevented by the cyclooxygenase inhibitors indomethacin ( 15 pmol/L), acetylsalicylate (3 mmol/L) or ibuprofen (200 pmol/L). On addition of chlorpromazine the liver releases increased amounts of prostaglandin D,; this increase does not occur in the presence of indomethacin.
At higher concentrations of chlorpromazine (100 pmolb) the inhibition of taurocholate clearance and bile flow is accompanied by only a moderate increase of portal pressure, and indomethacin is without effect. At this high concentration, substantial cell damage, as indicated by the release of lactate dehydrogenase, is present.
W e conclude that arachidonic acid-derived metabolites, notably prostanoids, are involved in the inhibition of bile flow and of taurocholate clearance observed at low concentrations of chlorpromazine. The data suggest that changes in the microcirculation are responsible for the impairment of the liver functions. At higher concentrations of chlorpromazine the cell toxicity of the drug becomes prominent. (HEPATOLOGY 1991; 13:2 16-221.)
Chlorpromazine is a widely used antipsychotic drug, which may cause hepatic dysfunction as a side effect (1-3). In perfused rat liver chlorpromazine causes a lowering of perfusate flow through the organ, a decreased rate of removal of sulfobromophthalein and taurocholate from the perfusate and a decrease in bile flow (4-6). These effects were ascribed to changes in the hepatic blood flow (4). However, later evidence suggests that the adverse effects of chlorpromazine may occur independently of the observed changes in liver hemodynamics (5, 6) and are primarily caused by structural changes of the liver plasma membrane (7-9).