EFFECT OF ETHANOL ON HEPATOBILIARY TRANSPORT OF CATIONIC DRUGS - A STUDY IN THE ISOLATED-PERFUSED RAT-LIVER, RAT HEPATOCYTES AND RAT MITOCHONDRIA

The effect of ethanol on the hepatic uptake of various cationic drugs was studied in isolated perfused rat livers, isolated rat hepatocytes and isolated rat liver mitochondria. In isolated rat hepatocytes and i n isolated perfused rat livers, the uptake of the model organic cation tri-n-butylmethylammonium was found to be markedly stimulated by etha nol in a concentration-dependent fashion. The uptake of tri-n-butylmet hylammonium at 1 mu M was increased to 120% and 137% at 0.5% (v/v, (=8 7 mM)) and 1% (v/v, (=174 mM)) ethanol, respectively. At 25 mu M, tri- n-butylmethylammonium uptake was increased to 124% and 152% at 0.5% (v /v) and 1% (v/v) of ethanol, respectively. The uptake of the organic c ations azidoprocainamide methoiodide, vecuronium, ORG 9426 and ORG 636 8, the anionic compound taurocholate and the uncharged compound ouabai n was not markedly increased at these ethanol concentrations. The mech anism of action of ethanol on the uptake of tri-n-butylmethylammonium was further studied. Competitive inhibitors for the type I organic cat ion uptake system, procainamide ethobromide and verapamil, almost comp letely blocked uptake of tri-n-butylmethylammonium (1 mu M) in the pre sence of 1% (v/v) ethanol, indicating that carrier-mediated uptake is still involved and that additional passive diffusion is unlikely. Neit her the plasma membrane potential nor the accumulation of the cation i n mitochondria was altered after ethanol treatment, suggesting that po tential driving forces for uptake and sequestration were not affected. Apart from ethanol, methanol (1%, v/v), propanol (1%, v/v) and dimeth yl sulfoxide (1%, v/v) also stimulated the uptake of tri-n-butylmethyl ammonium (at 1 mu M) in isolated rat hepatocytes to 117%, 124% and 122 % respectively. The results of our study indicate that ethanol selecti vely stimulates the uptake of the aliphatic organic cation tri-n-butyl methylammonium rather than through generally alterated hepatobiliary t ransport processes. (C) Journal of Hepatology.