CHARACTERIZATION OF TRANSPORT IN ISOLATED HUMAN HEPATOCYTES - A STUDYWITH THE BILE-ACID TAUROCHOLIC ACID, THE UNCHARGED OUABAIN AND THE ORGANIC CATIONS VECURONIUM AND ROCURONIUM
Gw. Sandker et al., CHARACTERIZATION OF TRANSPORT IN ISOLATED HUMAN HEPATOCYTES - A STUDYWITH THE BILE-ACID TAUROCHOLIC ACID, THE UNCHARGED OUABAIN AND THE ORGANIC CATIONS VECURONIUM AND ROCURONIUM, Biochemical pharmacology, 47(12), 1994, pp. 2193-2200
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.