Hedman A, Meijer D K
Department of Pharmacokinetics and Drug Delivery, University Centre for Pharmacy, Groningen Institute of Drug Studies, The Netherlands.
J Hepatol. 1998 Feb;28(2):240-9. doi: 10.1016/0168-8278(88)80011-4.
BACKGROUND/AIMS: Certain basic (cationic) drugs are known to interact with the hepatic transport, and renal and/or biliary clearance of cardiac glycosides. The mechanisms behind these interactions are not fully understood. In the present study our aim was to investigate the effects of the two diastereomers, quinidine and quinine, as well as the calcium antagonist verapamil, on the hepatobiliary elimination of digoxin and ouabain in the isolated perfused rat liver.
Livers from male, fasting Wistar rats were perfused by recirculation of Krebs-Henseleit bicarbonate buffer supplemented with 1% BSA. Disposition of digoxin or ouabain was studied at an initial perfusion medium concentration (Ci) of 100 or 10 nmol/l for digoxin and a Ci of 30 micromol/l for ouabain. The Ci of quinine, quinidine or verapamil was 50 micromol/l. Concentrations of the drugs in perfusion medium and bile were followed up to 2 h.
A marked reduction in the initial medium disappearance rate of digoxin and ouabain by quinine was found, whereas quinidine did not affect the hepatic disposition of the cardiac glycosides. The stereoselective inhibition of digoxin and ouabain clearance by quinine, and not by quinidine, was shown to be due to an effect on the hepatic uptake level rather than on the metabolic conversion and/or the biliary excretion steps. An allosteric type of inhibition by the basic drugs, exerted from the inside of the cells, is inferred. This interaction may occur at the sinusoidal plasma membrane on the level of multi-specific carrier proteins for cardiac glycosides and cationic drugs, as cloned recently by various groups.
A marked stereoselective difference was found in the effect of the stereoisomers quinidine and quinine on the hepatic uptake of digoxin and ouabain, quinine being the potent inhibitor.
背景/目的：已知某些碱性（阳离子）药物会与强心苷的肝脏转运以及肾脏和/或胆汁清除相互作用。这些相互作用背后的机制尚未完全了解。在本研究中，我们的目的是研究两种非对映异构体奎尼丁和奎宁以及钙拮抗剂维拉帕米对离体灌注大鼠肝脏中地高辛和哇巴因肝胆清除的影响。
雄性禁食Wistar大鼠的肝脏通过补充1%牛血清白蛋白的Krebs-Henseleit碳酸氢盐缓冲液再循环进行灌注。在地高辛初始灌注培养基浓度（Ci）为100或10 nmol/l以及哇巴因Ci为30 μmol/l的条件下研究地高辛或哇巴因的处置。奎宁、奎尼丁或维拉帕米的Ci为50 μmol/l。跟踪灌注培养基和胆汁中药物浓度长达2小时。
发现奎宁显著降低了地高辛和哇巴因的初始培养基消失率，而奎尼丁不影响强心苷的肝脏处置。结果表明，奎宁而非奎尼丁对地高辛和哇巴因清除的立体选择性抑制是由于对肝脏摄取水平的影响，而非对代谢转化和/或胆汁排泄步骤的影响。推断碱性药物从细胞内部施加的变构抑制类型。这种相互作用可能发生在窦状质膜上，在最近不同研究小组克隆的强心苷和阳离子药物多特异性载体蛋白水平上。
发现立体异构体奎尼丁和奎宁对地高辛和哇巴因肝脏摄取的影响存在显著的立体选择性差异，奎宁是强效抑制剂。
