College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 702-701, Republic of Korea.
Pharmacol Ther. 2013 Apr;138(1):142-54. doi: 10.1016/j.pharmthera.2013.01.006. Epub 2013 Jan 24.
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.
超过 40%的临床应用药物是有机阳离子（OCs），这些药物在生理 pH 值下带正电荷，最近的报告已经确定这些药物是膜转运体的底物。OC 通过膜转运体的转运可能在胃肠道吸收、向靶部位分布以及各种 OC 药物的胆汁和/或肾消除中发挥重要作用。大约 40 年前，据报道，大鼠中存在单季铵（mono QA）化合物的分子量（Mw）阈值为 200，以便大量（例如，>静脉注射剂量的 10%）排泄到胆汁中。众所周知，一些 OCs 与体内适当的内源性有机阴离子（如胆汁盐）相互作用形成亲脂性离子对复合物。离子对形成可能会影响与胆汁排泄相关的膜转运体对 OCs 的亲和力或结合。从这个意义上说，离子对形成与 Mw 阈值的存在之间的关联似乎值得研究。它假设在肝脏中存在胆汁盐的情况下，高 Mw mono QA 化合物（即>200）形成离子对，随后通过相关的胆小管转运体加速离子对复合物的转运。因此，本文将特别关注离子对形成假说，综述 OC 药物的转运。这些信息将加深对 OC 药物药代动力学的理解，以及内源性胆汁盐在高 Mw QA 药物解毒或 II 期代谢中的生理作用的理解。
