Transport of organic cationic drugs: Effect of ion-pair formation with bile salts on the biliary excretion and pharmacokinetics

More than 40% of clinically used drugs are organic cations (OCs), which are positively charged at a physiologic pH, and recent reports have established that these drugs are substrates of membrane transporters. The transport of OCs via membrane transporters may play important roles in gastrointestinal absorption, distribution to target sites, and biliary and/or renal elimination of various OC drugs. Almost 40 years ago, a molecular weight (Mw) threshold of 200 was reported to exist in rats for monoquaternary ammonium (mono QA) compounds to be substantially (e.g., >10% of iv dose) excreted to bile. It is well known that some OCs interact with appropriate endogenous organic anions in the body (e.g., bile salts) to form lipophilic ion-pair complexes. The ion-pair formation may influence the affinity or binding of OCs to membrane transporters that are relevant to biliary excretion. In that sense, the association of the ion-pair formation with the existence of the Mw threshold appears to be worthy of examination. It assumes the ion-pair formation of high Mw mono QA compounds (i.e., >200) in the presence of bile salts in the liver, followed by accelerated transport of the ion-pair complexes via relevant bile canalicular transporter(s). In this article, therefore, the transport of OC drugs will be reviewed with a special focus on the ion-pair formation hypothesis. Such information will deepen the understanding of the pharmacokinetics of OC drugs as well as the physiological roles of endogenous bile salts in the detoxification or phase II metabolism of high Mw QA drugs.