Protein-mediated hepatic uptake of rose bengal in analbuminemic mutant rats (NAR). Albumin is not indispensable to the protein-mediated transport of rose bengal.
Recent kinetic studies using in situ perfused rat liver suggested that the hepatic uptake of extensively albumin-bound ligands is mediated primarily by direct interaction of the albumin-ligand complex with the hepatocyte surface rather than by the small unbound fraction of ligand, as has been generally believed [Ockner et al., Am. J. Physiol. 245, G13 (1983)]. In order to investigate this mechanism in vivo, rose bengal (RB) was injected iv to the normal and Nagase analbuminemic mutant rats (NAR) and both the pharmacokinetic parameters and the serum protein binding parameters for the two groups were compared. The serum disappearance curves of RB in normal rats and NAR were almost superimposed, and no significant difference in various pharmacokinetic parameters including the hepatic uptake clearance (k12V1) was observed between the two groups. Nevertheless, the unbound fractions of RB in serum were approximately 4-fold (equilibrium dialysis method) and 10-fold (spectrophotometric method) higher than those in normal rats. However, in both groups of rats RB is extensively bound to plasma proteins and more than 99.8% of RB in the plasma exists as the protein-bound form. The intrinsic ability of the two groups of rats to take up unbound RB was compared using isolated liver cells. No significant difference between the two groups was observed in the initial velocity of uptake. From these findings, we concluded that the hepatic uptake of RB is primarily driven by the serum protein-bound form and not by the unbound form and that the serum protein-mediated uptake mechanism of RB was not specific only for serum albumin but also for other serum proteins.(ABSTRACT TRUNCATED AT 250 WORDS)
Tsao
S C
SC
Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
Sugiyama
Y
Y
Shinmura
K
K
Sawada
Y
Y
Nagase
S
S
Iga
T
T
Hanano
M
M
D000818:Animals; D001693:Biological Transport, Active; D002478:Cells, Cultured; D003956:Dialysis; D007275:Injections, Intravenous; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D009154:Mutation; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D012395:Rose Bengal / Q000378:metabolism* / Q000493:pharmacokinetics; D012709:Serum Albumin / Q000172:deficiency*; D013056:Spectrophotometry, Ultraviolet; D005719:gamma-Globulins / Q000378:metabolism
D011506:Proteins; D012709:Serum Albumin; D005719:gamma-Globulins; D012395:Rose Bengal