Elsevier

Biochemical Pharmacology

Volume 44, Issue 12, 15 December 1992, Pages 2323-2331
Biochemical Pharmacology

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

https://doi.org/10.1016/0006-2952(92)90676-AGet rights and content

Abstract

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 μM) of the presumed type I monovalent organic cation tri-n-butylmethylammonium were markedly different from those at relatively high concentrations (25 μM). Both the cardiac glycoside K-strophantoside and the bile acid taurocholate clearly reduced the uptake rate of tri-n-butylmethylamnonium at 25 μM 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 μM) and at relatively high concentrations (25 μM) 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 μM 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 hepacytes: tri-n- butylmethylammonium in a concentration range≤1 μ is mainly taken up by the type I uptake system and at concentrations range ≤25 μ also by system(s) that can be inhibited by taurocholate and K-strophantoside. Bulky amphipathic organic (type II) cations at concentrations <1 μare also transported by an uptake system that is inhibitable by cardiac glycosides but not by bile salts. At concentrations ⩾25 μM 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 taucholate 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.

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