CHARACTERIZATION OF THE UPTAKE OF ROCURONIUM AND DIGOXIN IN HUMAN HEPATOCYTES - CARRIER SPECIFICITY AND COMPARISON WITH IN-VIVO DATA

Mechanisms of drug transport in the liver have been investigated predo minantly in rodents. Most of the in vitro drug research in the liver i s performed in liver preparations of animals. The results of such expe riments frequently are discussed in relation to anticipated metabolic profiles in man, but these extrapolations are often inappropriate beca use of large interspecies differences in drug metabolism. In the prese nt 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 he patocytes. The extraction ratio for the intact liver was calculated fr om the measured uptake rates of the compounds in the human cells in vi tro and compared with published in vivo data. The initial hepatic extr action ratio, calculated from the in vitro uptake data for digoxin and rocuronium, very well reflected the initial extraction ratio for dist ribution in the liver in vivo in man. Uptake of 100 mu M rocuronium wa s inhibited by 40 mu M K-strophantoside (80% inhibition), and although not significantly, by 160 mu M procainamide ethobromide, whereas no i nhibitory effect was found in the presence of 160 mu M taurocholic aci d. In a previous study in rat hepatocytes, marked inhibition of digoxi n uptake by quinine and only minimal inhibition by the diastereomer qu inidine 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 indicat es clear species differences. This is the first study to investigate t he uptake mechanisms of organic cations and cardiac glycosides in huma n hepatocytes in some detail. The results show that uptake characteris tics of drugs found in rats can not be extrapolated directly to humans .