CHARACTERIZATION OF TRANSPORT IN ISOLATED HUMAN HEPATOCYTES - A STUDYWITH THE BILE-ACID TAUROCHOLIC ACID, THE UNCHARGED OUABAIN AND THE ORGANIC CATIONS VECURONIUM AND ROCURONIUM

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 the in vitro experiments quantitati vely reflect liver function in vivo in 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 r ate of taurocholic acid in isolated hepatocytes of both species was qu antitatively compatible with the reported liver clearance of the bile acid in vivo. Ouabain uptake rate in isolated human hepatocytes was lo wer than in rat hepatocytes. This species difference was in accordance with pharmacokinetic studies in vivo on 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 eff lux from human hepatocytes was comparable for the two short acting mus cle relaxants vecuronium and rocuronium. Since distribution to the liv er is considered to be a major factor in termination of action of vecu ronium and rocuronium these observations were in line with the human p harmacokinetic profiles. In conclusion, the uptake rate of the studied model compounds in human hepatocytes appeared to be lower than that i n rat hepatocytes. These observed transport rates reflected the relati ve hepatic transport rates observed in these species in the intact org anism, but the absolute Values in both species for some substrates may have been somewhat lower than calculated from in vivo data. It is con cluded that transport studies in isolated hepatocytes are suitable for comparative drug transport studies, but are less precise in the predi ction of quantitative membrane transport.