Kinetic analysis of hepatobiliary transport of organic anions in Eisai hyperbilirubinemic mutant rats

K Sathirakul, H Suzuki, K Yasuda, M Hanano, O Tagaya, T Horie and Y Sugiyama

Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.

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.

Volume 265, Issue 3, pp. 1301-1312, 06/01/1993
Copyright © 1993 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				Y. Kato, S. Takahara, S. Kato, Y. Kubo, Y. Sai, I. Tamai, H. Yabuuchi, and A. Tsuji Involvement of Multidrug Resistance-Associated Protein 2 (Abcc2) in Molecular Weight-Dependent Biliary Excretion of {beta}-Lactam Antibiotics Drug Metab. Dispos., June 1, 2008; 36(6): 1088 - 1096. [Abstract] [Full Text] [PDF]

				X.-Y. Chu, J. R. Strauss, M. A. Mariano, J. Li, D. J. Newton, X. Cai, R. W. Wang, J. Yabut, D. P. Hartley, D. C. Evans, et al. Characterization of Mice Lacking the Multidrug Resistance Protein Mrp2 (Abcc2) J. Pharmacol. Exp. Ther., May 1, 2006; 317(2): 579 - 589. [Abstract] [Full Text] [PDF]

				M. Hirano, K. Maeda, S. Matsushima, Y. Nozaki, H. Kusuhara, and Y. Sugiyama Involvement of BCRP (ABCG2) in the Biliary Excretion of Pitavastatin Mol. Pharmacol., September 1, 2005; 68(3): 800 - 807. [Abstract] [Full Text] [PDF]

				K. Ito, T. Koresawa, K. Nakano, and T. Horie Mrp2 is involved in benzylpenicillin-induced choleresis Am J Physiol Gastrointest Liver Physiol, July 1, 2004; 287(1): G42 - G49. [Abstract] [Full Text] [PDF]

				N. Mizuno, T. Niwa, Y. Yotsumoto, and Y. Sugiyama Impact of Drug Transporter Studies on Drug Discovery and Development Pharmacol. Rev., September 1, 2003; 55(3): 425 - 461. [Abstract] [Full Text] [PDF]

				D. R. Johnson, S. S. M. Habeebu, and C. D. Klaassen Increase in Bile Flow and Biliary Excretion of Glutathione-Derived Sulfhydryls in Rats by Drug-Metabolizing Enzyme Inducers Is Mediated by Multidrug Resistance Protein 2 Toxicol. Sci., March 1, 2002; 66(1): 16 - 26. [Abstract] [Full Text] [PDF]

				L. Huang and M. Vore Multidrug Resistance P-Glycoprotein 2 Is Essential for the Biliary Excretion of Indocyanine Green Drug Metab. Dispos., April 13, 2001; 29(5): 634 - 637. [Abstract] [Full Text]

				M. Lund, L. Kang, N. Tygstrup, A. W. Wolkoff, and P. Ott Effects of LPS on transport of indocyanine green and alanine uptake in perfused rat liver Am J Physiol Gastrointest Liver Physiol, July 1, 1999; 277(1): G91 - G100. [Abstract] [Full Text] [PDF]

				M. Murata, I. Tamai, Y. Sai, O. Nagata, H. Kato, Y. Sugiyama, and A. Tsuji Hepatobiliary Transport Kinetics of HSR-903, a New Quinolone Antibacterial Agent Drug Metab. Dispos., November 1, 1998; 26(11): 1113 - 1119. [Abstract] [Full Text]

				H. Yabuuchi, I. Tamai, K. Morita, T. Kouda, K.-I. Miyamoto, E. Takeda, and A. Tsuji Hepatic Sinusoidal Membrane Transport of Anionic Drugs Mediated by Anion Transporter Npt1 J. Pharmacol. Exp. Ther., September 1, 1998; 286(3): 1391 - 1396. [Abstract] [Full Text]

				T. Hirohashi, H. Suzuki, K. Ito, K. Ogawa, K. Kume, T. Shimizu, and Y. Sugiyama Hepatic Expression of Multidrug Resistance-Associated Protein-Like Proteins Maintained in Eisai Hyperbilirubinemic Rats Mol. Pharmacol., June 1, 1998; 53(6): 1068 - 1075. [Abstract] [Full Text]

				H. Imawaka and Y. Sugiyama Kinetic Study of the Hepatobiliary Transport of a New Prostaglandin Receptor Agonist J. Pharmacol. Exp. Ther., March 1, 1998; 284(3): 949 - 957. [Abstract] [Full Text]

				H. Sasabe, A. Tsuji, and Y. Sugiyama Carrier-Mediated Mechanism for the Biliary Excretion of the Quinolone Antibiotic Grepafloxacin and Its Glucuronide in Rats J. Pharmacol. Exp. Ther., March 1, 1998; 284(3): 1033 - 1039. [Abstract] [Full Text]

				W. Geng, A. J. Schwab, T. Horie, C. A. Goresky, and K. S. Pang Hepatic Uptake of Bromosulfophthalein-Glutathione in Perfused Eisai Hyperbilirubinemic Mutant Rat Liver: A Multiple-Indicator Dilution Study J. Pharmacol. Exp. Ther., February 1, 1998; 284(2): 480 - 492. [Abstract] [Full Text]

				H. Sasabe, Y. Kato, A. Tsuji, and Y. Sugiyama Stereoselective Hepatobiliary Transport of the Quinolone Antibiotic Grepafloxacin and Its Glucuronide in the Rat J. Pharmacol. Exp. Ther., February 1, 1998; 284(2): 661 - 668. [Abstract] [Full Text]

				K. Ito, H. Suzuki, T. Hirohashi, K. Kume, T. Shimizu, and Y. Sugiyama Functional Analysis of a Canalicular Multispecific Organic Anion Transporter Cloned from Rat Liver J. Biol. Chem., January 16, 1998; 273(3): 1684 - 1688. [Abstract] [Full Text] [PDF]

				K. Niinuma, O. Takenaka, T. Horie, K. Kobayashi, Y. Kato, H. Suzuki, and Y. Sugiyama Kinetic Analysis of the Primary Active Transport of Conjugated Metabolites Across the Bile Canalicular Membrane: Comparative Study of S-(2,4-Dinitrophenyl)-glutathione and 6-Hydroxy-5,7-dimethyl-2-methylamino4-(3-pyridylmethyl)benzothiazole Glucuronide J. Pharmacol. Exp. Ther., August 1, 1997; 282(2): 866 - 872. [Abstract] [Full Text]

				T. Yamada, K. Niinuma, M. Lemaire, T. Terasaki, and Y. Sugiyama CARRIER-MEDIATED HEPATIC UPTAKE OF THE CATIONIC CYCLOPEPTIDE, OCTREOTIDE, IN RATS. Comparison between In Vivo and In Vitro Drug Metab. Dispos., May 1, 1997; 25(5): 536 - 543. [Abstract] [Full Text]

				X.-Y. Chu, Y. Kato, K. Niinuma, K.-I. Sudo, H. Hakusui, and Y. Sugiyama Multispecific Organic Anion Transporter Is Responsible for the Biliary Excretion of the Camptothecin Derivative Irinotecan and its Metabolites in Rats J. Pharmacol. Exp. Ther., April 1, 1997; 281(1): 304 - 314. [Abstract] [Full Text]

				H. Ishizuka, K. Konno, H. Naganuma, K. Sasahara, Y. Kawahara, K. Niinuma, H. Suzuki, and Y. Sugiyama Temocaprilat, a Novel Angiotensin-Converting Enzyme Inhibitor, is Excreted in Bile via an ATP-dependent Active Transporter (cMOAT) That is Deficient in Eisai Hyperbilirubinemic Mutant Rats (EHBR) J. Pharmacol. Exp. Ther., March 1, 1997; 280(3): 1304 - 1311. [Abstract] [Full Text]