A multispecific uptake system for taurocholate, cardiac glycosides and cationic drugs in the liver

To test the hypothesis of multiplicity in carrier-mediated uptake mechanisms for organic cations in the liver and to study the possible relation with bile acid and cardiac glycoside uptake mechanisms, mutual interaction during uptake of various radiolabeled quaternary amines has been studied in isolated rat hepatocytes. Inhibition patterns at low concentrations (1 muM) of the presumed type I monovalent organic cation tri-n-butylmethylammonium were markedly different from those at relatively high concentrations (25 muM). Both the cardiac glycoside K-strophantoside and the bile acid taurocholate clearly reduced the uptake rate of tri-n-butylmethylammonium at 25 muM whereas these agents completely failed to reduce the uptake at low concentrations of the cation. Subsequently, inhibition of uptake of some multivalent amphipathic organic cations (muscle relaxants) for the type II uptake system was investigated. It was found that the uptake of these muscle relaxants both at tracer concentrations (<1 muM) and at relatively high concentrations (25 muM) was decreased in the presence of low concentrations of the cardiac glycoside K-strophantoside, while taurocholate only inhibited the uptake at the concentration range >25 muM of the muscle relaxants, Procainamide ethobromide, a typical type I organic cation, did not affect the uptake either at the low or high concentration range of the muscle relaxants. It is concluded that for each of the type I-like compounds and type II-like compounds tested at least two systems are involved in uptake into hepatocytes: tri-n-butylmethylammonium in a concentration range less-than-or-equal-to 1 muM is mainly taken up by the type I uptake system and at concentrations greater-than-or-equal-to 25 muM also by system(s) that can be inhibited by taurocholate and K-strophantoside. Bulky amphipathic organic (type II) cations at concentrations 25 muM these compounds are predominantly accommodated by an uptake system that possibly mediates uptake of both cardiac glycosides and bile acids. This concept was supported by the observation that both type II organic cations and bile salts can inhibit ouabain uptake, while type II organic cations as well as the cardiac glycosides reduce taurocholate uptake rate. The present data support the idea that the liver seems to be equipped with a ''multispecific'' uptake system that transports hydrophobic compounds irrespective of charge, including some type I and type II organic cations at relatively high substrate concentrations.