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

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.

Uptake and Intracellular Binding of Lipophilic Amine Drugs by Isolated Rat Hepatocytes and Implications for Prediction of in Vivo Metabolic Clearance

“…It has been observed that some cationic drugs, including propranolol and imipramine, may undergo cellular uptake by active transport (Meijer et al, 1990;Nakamura et al, 1994;van Montfoort et al, 2003;Chandra and Brouwer, 2004) involving members of the organic anion-transporting polypeptide and organic cation transporter families. It is of interest that the uptake of imipramine was not affected by treatment with rotenone, an inhibitor of ATP-dependent transport (consistent with the involvement of solute-linked carrier organic anion transporter rather than the ATP-binding cassette subfamily C family of transporter proteins).…”

Contribution of the murine mdr1a P-glycoprotein to hepatobiliary and intestinal elimination of cationic drugs as measured in mice with an mdr1a gene disruption

“…However, renal secretion of vecuronium contributed only minimally to the total body elimina- tion of the type 2 cationic compound as compared with the smaller type 1 cationic drugs; this finding is in accordance with those of other studies. 15,39,40 The exact role of P-glycoprotein in the kidney, with regard to renal drug secretion, is still under investigation both in vivo and in vitro. 19,[41][42][43] The contribution of P-glycoprotein to renal drug elimination may in part be obscured by an abundant presence of other transport mechanisms in the proximal tubule kidney cells that also contribute to renal secretion of cationic drugs.…”

ATP‐dependent transport of amphiphilic cations across the hepatocyte canalicular membrane mediated by mdr1 P‐glycoprotein

“…The liver plays a central role in the disposition of exogenous and endogenous compounds [ 18,191. Primary-active ATP-dependent transport is the major mechanism to secrete toxic and non-toxic, exogenous as well as endogenous substances across the hepatocyte canalicular membrane into bile [4,6,15,.…”