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 in isolated perfused rat livers, the uptake of the model organic cation tri-n-butylmethylammonium was found to be markedly stimulated by ethanol in a concentration-dependent fashion. The uptake of tri-n-butylmethylammonium at 1 microM was increased to 120% and 137% at 0.5% (v/v, (= 87 mM)) and 1% (v/v. (= 174 mM)) ethanol, respectively. At 25 microM, 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 cations azidoprocainamide methoiodide, vecuronium, ORG 9426 and ORG 6368, the anionic compound taurocholate and the uncharged compound ouabain was not markedly increased at these ethanol concentrations. The mechanism of action of ethanol on the uptake of tri-n-butylmethylammonium was further studied. Competitive inhibitors for the type I organic cation uptake system, procainamide ethobromide and verapamil, almost completely blocked uptake of tri-n-butylmethylammonium (1 microM) in the presence of 1% (v/v) ethanol, indicating that carrier-mediated uptake is still involved and that additional passive diffusion is unlikely. Neither the plasma membrane potential nor the accumulation of the cation in mitochondria was altered after ethanol treatment, suggesting that potential driving forces for uptake and sequestration were not affected.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Pharmacology and Therapeutics, Groningen State University, The Netherlands.
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Steen
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Merema
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DK
Meijer
D000079:Acetaldehyde / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D008930:Mitochondria, Liver / Q000378:metabolism* / Q000648:ultrastructure; D011342:Procainamide / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D014700:Verapamil / Q000494:pharmacology
D000644:Quaternary Ammonium Compounds; C043902:tri-n-butylmethylammonium; D000431:Ethanol; D014700:Verapamil; D000079:Acetaldehyde; D011342:Procainamide