Kinetic analysis of hepatobiliary transport of organic anions in Eisai hyperbilirubinemic mutant rats.
The hepatobiliary transport of nonmetabolizable organic anions [cefodizime, dibromosulfophthalein, and indocyanine green (ICG)] was kinetically analyzed in Eisai hyperbilirubinemic rats (EHBR; Sprague-Dawley-derived mutant rats with conjugated hyperbilirubinemia). In EHBR, the biliary excretion of these anions was remarkably impaired, whereas the alteration in initial plasma disappearance was minimal. The kinetic analysis of the disposition of these ligands revealed 1) that the transport rate via bile canalicular membrane was severely impaired in EHBR for cefodizime and dibromosulfophthalein and 2) that the intracellular transport rate of ICG was decreased in EHBR, which contributed more than the decrease in the canalicular membrane transport to the net reduction of the excretion rate of ICG in EHBR. The latter finding was also supported by the in vitro results; the binding of ICG to ligandin(s) in EHBR was less extensive compared with that in normal rats, resulting in the higher distribution of ICG to organelle. Because the ligand molecules bound to organelle diffuse within the cells much more slowly than the molecules in the cytosol, the higher distribution of ICG to organelle in EHBR results in the reduction in the intracellular transport rate. These results indicate that the differential impairment mechanisms can be proposed for the excretion of organic anions: One is the impairment in the transport rate across the canalicular membrane, the other is the impairment in the intracellular transport rate.
Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
K
K
Sathirakul
H
H
Suzuki
K
K
Yasuda
M
M
Hanano
O
O
Tagaya
T
T
Horie
Y
Y
Sugiyama
D000818:Animals; D000838:Anions; D001652:Bile Ducts / Q000378:metabolism*; D001663:Bilirubin / Q000097:blood / Q000378:metabolism; D001692:Biological Transport; D001798:Blood Proteins / Q000378:metabolism; D002439:Cefotaxime / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D003600:Cytosol / Q000378:metabolism; D006932:Hyperbilirubinemia / Q000378:metabolism*; D007208:Indocyanine Green / Q000378:metabolism / Q000493:pharmacokinetics*; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D051381:Rats; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley; D013448:Sulfobromophthalein / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics
D000838:Anions; D001798:Blood Proteins; D013448:Sulfobromophthalein; C012479:dibromosulphthalein; D007208:Indocyanine Green; D002439:Cefotaxime; D001663:Bilirubin; C033356:cefodizime