Okudaira K, Sawada Y, Sugiyama Y, Iga T, Hanano M
Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
Biochem Pharmacol. 1988 Aug 1;37(15):2949-55. doi: 10.1016/0006-2952(88)90280-8.
The effects of some basic and acidic drugs on the hepatic uptake of digoxin and ouabain were studied in isolated rat hepatocytes. Digoxin accumulated against a concentration gradient, and its initial uptake was energy- and temperature-dependent. Digoxin competitively inhibited the uptake of ouabain (Ki = 1.3 microM), which was reported to be transported by a carrier-mediated active transport system. All basic drugs tested (verapamil, dipyridamole, amiodarone, nifedipine, diltiazem, ajmaline, chlorpromazine, imipramine, disopyramide, quinidine, procainamide, propranolol and lidocaine: 50 microM) except for procainamide, propranolol and lidocaine significantly (P less than 0.05) reduced the uptake of digoxin, whereas acidic drugs (salicylic acid and phenytoin) had no effect. The same inhibitory effects were observed for ouabain uptake, whereas the uptake of alanine was not changed by these drugs. Quinidine inhibited the uptake of ouabain in a noncompetitive manner (Ki = 88 microM). These basic drugs had no effect on the permeability of the cells assessed by the trypan blue exclusion test and succinate-simulated oxygen consumption. But carbonylcyanide-m-chlorophenyl hydrazone-stimulated oxygen consumption decreased in the presence of some basic drugs and correlated with their inhibitory effects on digoxin uptake. Therefore, one of the mechanisms of the inhibitory effects of these drugs on digoxin uptake was the inhibition of oxidative phosphorylation. These basic drugs had no effect on the microtubular system, which was assessed by the measurement of tubulin polymerization and colchicine binding to tubulin. The results of our study suggested that many basic drugs have a potential to inhibit the hepatocellular uptake of cardiac glycosides.
在离体大鼠肝细胞中研究了一些碱性和酸性药物对地高辛和哇巴因肝脏摄取的影响。地高辛逆浓度梯度蓄积，其初始摄取依赖能量和温度。地高辛竞争性抑制哇巴因的摄取（Ki = 1.3微摩尔），据报道哇巴因是通过载体介导的主动转运系统转运的。除普鲁卡因胺、普萘洛尔和利多卡因外，所有测试的碱性药物（维拉帕米、双嘧达莫、胺碘酮、硝苯地平、地尔硫䓬、阿义马林、氯丙嗪、丙咪嗪、双异丙吡胺、奎尼丁、普鲁卡因胺、普萘洛尔和利多卡因：50微摩尔）均显著（P<0.05）降低地高辛的摄取，而酸性药物（水杨酸和苯妥英）则无影响。对哇巴因摄取观察到相同的抑制作用，而这些药物对丙氨酸的摄取没有改变。奎尼丁以非竞争性方式抑制哇巴因的摄取（Ki = 88微摩尔）。这些碱性药物对通过台盼蓝排斥试验和琥珀酸模拟的氧消耗评估的细胞通透性没有影响。但在一些碱性药物存在下，羰基氰化物-间氯苯腙刺激的氧消耗降低，且与它们对地高辛摄取的抑制作用相关。因此，这些药物对地高辛摄取抑制作用的机制之一是抑制氧化磷酸化。这些碱性药物对微管系统没有影响，微管系统是通过测量微管蛋白聚合和秋水仙碱与微管蛋白的结合来评估的。我们的研究结果表明，许多碱性药物有抑制心肌苷肝细胞摄取的潜力。
