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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In order to identify polypeptides interacting with organic cations like PAEB the photolabile derivative J-azid0-N-[2diethyl([~H]methyI)ethyl]benzan1ideiodide with a specific radioactivity of 4.3 Ci/mmol was synthesized. Photolysis of this derivative using a Rayonet RPR 100 reactor with a maximum emission at 300 nm obeyed first order kinetics with t i n = 13.5 min. The photochemical properties of this addo-derivative of PAEB indicate that it may be well suited for the identification of binding polypeptides by photoaffinity labeling studies. Procainamidethobromide (PAEB) and its N-acetyl derivative (APAEB) have been widely used as imodel compounds for the study of hepato-biliary transport of organic cations'-". The studies revealed that the hepatic uptake of these organic cations satisfies the criteria for carrier-mediated transport.

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