Abstract

Mechanisms of drug transport in the liver have been investigated predominantly in rodents. Most of the in vitro drug research in the liver is performed in liver preparations of animals. The results of such experiments frequently are discussed in relation to anticipated metabolic profiles in man, but these extrapolations are often inappropriate because of large interspecies differences in drug metabolism. In the present study, the mechanisms and specificity of the uptake of the organic cation rocuronium and the cardiac glycoside digoxin were investigated in human hepatocytes and were compared with results obtained in rat hepatocytes. The extraction ratio for the intact liver was calculated from the measured uptake rates of the compounds in the human cells in vitro and compared with published in vivo data. The initial hepatic extraction ratio, calculated from the in vitro uptake data for digoxin and rocuronium, very well reflected the initial extraction ratio for distribution in the liver in vivo in man. Uptake of 100 μM rocuronium was inhibited by 40 μM K-strophantoside (80% inhibition), and although not significantly, by 160 μM procainamide ethobromide, whereas no inhibitory effect was found in the presence of 160 μM taurocholic acid. In a previous study in rat hepatocytes, marked inhibition of digoxin uptake by quinine and only minimal inhibition by the diastereomer quinidine was demonstrated, showing clear stereoselectivity in transport inhibition. Unexpectedly, the uptake of digoxin in human hepatocytes was not inhibited significantly by quinidine or quinine, which indicates clear species differences. This is the first study to investigate the uptake mechanisms of organic cations and cardiac glycosides in human hepatocytes in some detail. The results show that uptake characteristics of drugs found in rats can not be extrapolated directly to humans.