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Vol. 285, Issue 2, 506-510, May 1998
Groningen Institute for Drug Studies, Department of
Pharmacokinetics and Drug Delivery, University Centre for Pharmacy
(P.O., M.M., I.H.H., J.H.P., D.K.F.M., G.M.M.G.), 9713 AV Groningen,
The Netherlands and
Division of Hepatobiliary Surgery and Liver
Transplantation, Department of Surgery, University Hospital (M.J.H.S.),
9713 EZ Groningen, The Netherlands.
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.
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