Characterization of transport in isolated human hepatocytes. A study with the bile acid taurocholic acid, the uncharged ouabain and the organic cations vecuronium and rocuronium.
Characterization of transport in isolated human hepatocytes. A study with the bile acid taurocholic acid, the uncharged ouabain and the organic cations vecuronium and rocuronium.
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DOI：
10.1016/0006-2952(94)90255-0
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发表时间：
1994-06
影响因子：
5.8
通讯作者：
Gerrie W. Sandker;B. Weert;P. Olinga;Henke Wolters;M. Slooff;D. Meijer;G. Groothuis
中科院分区：
文献类型：
--
作者：
Gerrie W. Sandker;B. Weert;P. Olinga;Henke Wolters;M. Slooff;D. Meijer;G. Groothuis
在分离的人肝细胞中测量了三类底物的摄取和流出，并与大鼠肝细胞中的摄取和流出进行比较。此外，还研究了体外实验定量反映两个物种体内肝功能的程度。分离的人肝细胞对阴离子胆汁酸牛磺胆酸的吸收率比在分离的大鼠肝细胞中观察到的要低得多。人肝细胞和肝质膜囊泡中的牛磺胆酸摄取均表现出钠依赖性。两个物种的分离肝细胞中牛磺胆酸的摄取率与报道的体内胆汁酸的肝脏清除率定量一致。分离的人肝细胞中哇巴因的摄取率低于大鼠肝细胞中的摄取率。这种物种差异与人和大鼠体内哇巴因肝清除的药代动力学研究一致。人肝细胞对维库溴铵的摄取比大鼠肝细胞低约十分之一。两种短效肌松药维库溴铵和罗库溴铵的人体肝细胞摄取和流出量相当。由于肝脏分布被认为是维库溴铵和罗库溴铵作用终止的主要因素，这些观察结果与人类药代动力学特征一致。总之，人肝细胞中所研究的模型化合物的摄取率似乎低于大鼠肝细胞中的摄取率。这些观察到的转运速率反映了在完整生物体中这些物种中观察到的相对肝脏转运速率，但是两个物种中某些底物的绝对值可能略低于根据体内数据计算的值。结论是，分离肝细胞中的转运研究适用于比较药物转运研究，但在定量膜转运的预测方面不太精确。
The uptake and efflux of three categories of substrates were measured in isolated human hepatocytes and compared to those in rat hepatocytes. In addition, the extent to which thein vitroexperiments quantitatively reflect liver functionin vivoin both species was investigated. The anionic bile acid taurocholic acid was taken up by isolated human hepatocytes at a considerably lower rate than observed in isolated rat hepatocytes. Taurocholic acid uptake both in human hepatocytes and in liver plasma membrane vesicles showed sodium dependency. The uptake rate of taurocholic acid in isolated hepatocytes of both species was quantitatively compatible with the reported liver clearance of the bile acidin vivo. Ouabain uptake rate in isolated human hepatocytes was lower than in rat hepatocytes. This species difference was in accordance with pharmacokinetic studiesin vivoon hepatic clearance of ouabain in man and rat. Uptake of vecuronium into human hepatocytes was about a factor of 10 lower than that in rat hepatocytes. Uptake into and efflux from human hepatocytes was comparable for the two short acting muscle relaxants vecuronium and rocuronium. Since distribution to the liver is considered to be a major factor in termination of action of vecuronium and rocuronium these observations were in line with the human pharmacokinetic profiles. In conclusion, the uptake rate of the studied model compounds in human hepatocytes appeared to be lower than that in rat hepatocytes. These observed transport rates reflected the relative hepatic transport rates observed in these species in the intact organism, but the absolute values in both species for some substrates may have been somewhat lower than calculated fromin vivodata. It is concluded that transport studies in isolated hepatocytes are suitable for comparative drug transport studies, but are less precise in the prediction of quantitative membrane transport.