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Carrier-mediated transport in the hepatic distribution and elimination of drugs, with special reference to the category of organic cations

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Abstract

Carrier-mediated transport of drugs occurs in various tissues in the body and may largely affect the rate of distribution and elimination. Saturable translocation mechanisms allowing competitive interactions have been identified in the kidneys (tubular secretion), mucosal cells in the gut (intestinal absorption and secretion), choroid plexus (removal of drug from the cerebrospinal fluid), and liver (hepatobiliary excretion). Drugs with quaternary and tertiary amine groups represent the large category of organic cations that can be transported via such mechanisms. The hepatic and to a lesser extent the intestinal cation carrier systems preferentially recognize relatively large molecular weight amphipathic compounds. In the case of multivalent cationic drugs, efficient transport only occurs if large hydrophobic ring structures provide a sufficient lipophilicity-hydrophilicity balance within the drug molecule. At least two separate carrier systems for hepatic uptake of organic cations have been identified through kinetic and photoaffinity labeling studies. In addition absorptive endocytosis may play a role that along with proton-antiport systems and membrane potential driven transport may lead to intracellular sequestration in lysosomes and mitochondria. Concentration gradients of inorganic ions may represent the driving forces for hepatic uptake and biliary excretion of drugs. Recent studies that aim to the identification of potential membrane carrier proteins indicate multiple carriers for organic anions, cations, and uncharged compounds with molecular weights around 50,000 Da. They may represent a family of closely related proteins exhibiting overlapping substrate specificity or, alternatively, an aspecific transport system that mediates translocation of various forms of drugs coupled with inorganic ions. Consequently, extensive pharmacokinetic interactions can be anticipated at the level of uptake and secretion of drugs regardless of their charge.

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  1. Department of Pharmacology and Therapeutics, University Center for Pharmacy, Ant. Deusinglaan 2, 9713, AW, Groningen, The Netherlands

    Dirk K. F. Meijer & Wim E. M. Mol

  2. Institut für Organische Chemie und Biochemie, Universität Freiburg, West Germany

    Michael Müller & Gerhart Kurz

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Meijer, D.K.F., Mol, W.E.M., Müller, M. et al. Carrier-mediated transport in the hepatic distribution and elimination of drugs, with special reference to the category of organic cations. Journal of Pharmacokinetics and Biopharmaceutics 18, 35–70 (1990). https://doi.org/10.1007/BF01063621

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