P. Olinga et al., CHARACTERIZATION OF THE UPTAKE OF ROCURONIUM AND DIGOXIN IN HUMAN HEPATOCYTES - CARRIER SPECIFICITY AND COMPARISON WITH IN-VIVO DATA, The Journal of pharmacology and experimental therapeutics, 285(2), 1998, pp. 506-510
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
.