Semin Liver Dis 2000; Volume 20(Number 03): 251-264
DOI: 10.1055/s-2000-8408
Copyright © 2000 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Transport of Drugs Across the Hepatic Sinusoidal Membrane: Sinusoidal Drug Influx and Efflux in the Liver

HIROSHI. SUZUKI, YUICHI. SUGIYAMA
  • From the Graduate School of Pharmaceutical Sciences, The University of Tokyo, and The Core Research for Evolutional Sciences and Technology of Japan Sciences and Technology Corporation, Tokyo, Japan
Further Information

Publication History

Publication Date:
31 December 2000 (online)

ABSTRACT

The liver plays an important role in the detoxification of xenobiotics. Recently, many secondary active transporters responsible for sinusoidal drug uptake have been cloned and their transport properties have been determined. These include rat and human Na+-taurocholate cotransporting polypeptides, rat and human organic anion transporting polypeptides, rat and human prostaglandin transporters, rat organic anion transporters, and rat and human organic cation transporters. In addition, it has been suggested that the expression of multi-drug resistance associated protein 3, a primary active transporter responsible for the cellular extrusion of organic anions, on the sinusoidal membrane is induced under cholestatic conditions. In this article, drug transport across the sinusoidal membrane is summarized, particularly focusing on the molecular mechanism of transport.

REFERENCES

  • 1 Yamazaki M, Akiyama S, Nishigaki R. Uptake is the rate-limiting step in the overall hepatic eliminaion of pravastatin at steady-state in rats.  Pharm Res . 1996;  13 1559-1564
  • 2 Iwatsubo T, Suzuki H, Sugiyama Y. Determination of the rate-limiting step in the hepatic elimination of YM796 by isolated rat hepatocytes.  Pharm Res . 1999;  16 110-116
  • 3 Petzinger E. Transport of organic anions in the liver. An update on bile acid, fatty acid, monocarboxylate, anionic amino acid, cholephilic organic anion, and anionic drug transport.  Rev Physiol Biochem Pharmacol . 1994;  123 47-211
  • 4 Oude Elferink R PJ, Meijer D KF, Kuipers F. Hepatobiliary secretion of organic compounds; molecular mechanisms of membrane transport.  Biochim Biophys Acta . 1995;  1241 215-268
  • 5 Meier P J, Eckhardt U, Schroeder A. Substrate specificity of sinusoidal bile acid and organic anion uptake systems in rat and human liver.  Hepatol . 1997;  26 1667-1677
  • 6 Muller M, Jansen P LM. Molecular aspects of hepatobiliary transport.  Am J Physiol . 1997;  272 G1285-G1303
  • 7 Meijer D KF, Jansen P LM, Groothuis G MM. Hepatobiliary disposition and targeting of drugs and genes.  In: Bircher J, Benhamou JP, McIntyre N, et al. (eds). Oxford textbook of clinical hepatology, 2nd ed, Vol 1. Oxford: Oxford Univesity Press, 1999: 87-144
  • 8 Kullak-Ublick G A. Regulation of organic anion and drug transporters of the sinusoidal mambrane.  J Hepatol . 1999;  31 563-573
  • 9 Schroeder A, Eckhardt U, Stieger B. Substrate specificity of the rat liver Na+-bile salt cotransporter in Xenopus laevis oocytes and in CHO cells.  Am J Physiol . 1998;  274 G370-G375
  • 10 Horz J A, Honscha W, Petzinger E. Bumetanide is not transported by the Ntcp or by the oatp: Evidence for a third organic anion transporter in rat liver cells.  Biochim Biophys Acta . 1996;  1300 114-118
  • 11 Imawaka H, Sugiyama Y. Kinetic study of the hepatobiliary transport of a new prostaglandin receptor agonist.  J Pharmacol Exp Ther . 1998;  284 949-957
  • 12 Kullak-Ublick G A, Glasa J, Boker C. Chlorambucil-taurocholate is transported by bile acid carriers expressed in human hepatocellular carcinomas.  Gastroenterol . 1997;  113 1295-1305
  • 13 Kramer W, Wess G. Bile acid transport systems as pharmaceutical targets.  Eur J Clin Invest . 1996;  26 715-132
  • 14 Kramer W, Wess G, Ehnsen A. Modified bile acids as carriers for peptides and drugs.  J Control Rel . 1997;  46 17-30
  • 15 Suzuki H, Sugiyama Y. Transporters for bile acids and organic anions. In: Amidon G and Sadee W (eds). Membrane transprters as drug targets New York: Kluwer Academic/Plenum Publishers, 1999: 387-439
  • 16 Friesema E CH, Docter R, Moerings E PCM. Identification of thyroid hormone transporters.  Biochim Biophys Res Commun . 1999;  254 497-501
  • 17 Eckhardt U, Schroeder A, Stieger B. Polyspecific substrate uptake by the hepatic organic anion transporter Oatp1 in stably transfected CHO cells.  Am J Physiol . 1999;  276 G1037-G1042
  • 18 Reichel C, Gao B, van Montfoort J. Localization and function of the organic anion-transporting polypeptide oatp2 in rat liver.  Gastroenterol . 1999;  117 688-695
  • 19 Pang K S, Wang P J, Chung A YK. The modified dipeptide, enalapril, an angiotensin-converting enzyme inhibitor, is transported by the rat liver organic anion transport protein.  Hepatol . 1998;  28 1341-1346
  • 20 Ishizuka H, Konno K, Naganuma H. Transport of temocaprilat into rat hepatocytes: Role of organic anion transporting polypeptide.  J Pharmacol Exp Ther . 1998;  287 37-42
  • 21 Cvetkovic M, Leake B, Fromm M F. Oatp and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine.  Drug Metab Dispos . 1999;  27 866-871
  • 22 Hsiang B, Zhu Y, Wang Z. A novel human hepatic organic anion transporting polypeptide (OATP2): Identification of a liver-specifid human organic anion transporting polypeptide and identification of rat and human hydroxymethylglutaryl-CoA reductase inhibitor transporters.  J Biol Chem . 1999;  274 37161-37168
  • 23 Kontaxi M, Eckhardt U, Hagenbuch B. Uptake of the mycotoxin ochratoxin A in liver cells occur via the cloned organic anion transporting polypeptide.  J Pharmacol Exp Ther . 1996;  279 1507-1513
  • 24 Li L, Lee T K, Meier P J. Identification of glutathione as a driving force and leukotriene C4 as a substrate for oatp1, the hepatic sinusoidal organic solute transporter.  J Biol Chem . 1998;  273 16184-16191
  • 25 Satlin L M, Amin V, Wolkoff A W. Organic anion transporting polypeptide mediates organic anion/HCO3 2- exchange.  J Biol Chem . 1997;  272 26340-26345
  • 26 Shi X, Bai S, Ford A C. Stable inducible expression of a functional rat liver organic anion transporter protein in HeLa cells.  J Biol Chem . 1995;  270 25591-25595
  • 27 Kakyo M, Sakagami H, Nishio T. Immunohistochemical distribution and functional characterization of an organic anion transporting polypeptide 2 (oatp2).  FEBS Lett . 1999;  445 343-346
  • 28 Abe T, Kakyo M, Sakagami H. Molecular characterization and tissue distribution of a new organic anion transporter subtype (oatp3) that transports thyroid hormones and taurocholate and comparison with oatp2.  J Biol Chem . 1998;  273 22395-22401
  • 29 Kullak-Ublick G A, Hagenbuch B, Stieger B. Molecular and funcional characterization of an organic anion transporting polypeptide cloned from human liver.  Gastroenterol . 1995;  109 1274-1282
  • 30 Kullak-Ublick G A, Fisch T, Oswald M. Dehydroepiandrosterone sulfate (DHEAS): Identification of a carrier protein in human liver and brain.  FEBS Lett . 1998;  424 173-176
  • 31 Abe T, Kakyo M, Tokui T. Identification of a novel gene family encoding human liver-specific organic anion transporter LST-1.  J Biol Chem . 1999;  274 17159-17163
  • 32 König J, Cui Y, Nies A T. A novel human organic anion transporting polypeptide localized to the basolateral hepatocyte membrane.  Am J Physiol . 2000;  278 G156-G164
  • 33 Kakyo M, Unno M, Tokui T. Molecular characterization and functional regulation of a novel rat liver-specific organic anion transporter rlst-1.  Gastroenterol . 1999;  117 770-775
  • 34 Saito H, Masuda S, Inui K. Cloning and functional characterization of a novel rat organic anion transporter mediating basolateral uptake of methotrexate in the kidney.  J Biol Chem . 1996;  271 20719-20725
  • 35 Masuda S, Ibaramoto K, Takeuchi A. Cloning and functional characterization of a new multispecific organic anion transporter, OAT-K2, in rat kidney.  Mol Pharmacol . 1999;  55 743-752
  • 36 Sekine T, Watanabe N, Hosoyamada M. Expression cloning and characterization of a novel multispecific organic anion transporter.  J Biol Chem . 1997;  272 18526-18529
  • 37 Sweet D H, Wolff N A, Pritchard J B. Expression cloning and characterization of ROAT1, the basolateral organic anion transporter in rat kidney.  J Biol Chem . 1997;  272 30088-30095
  • 38 Apiwattanakul N, Sekine T, Chairoungdua A. Transport properties of nonsteroidal anti-inflammatory drugs by organic anion transporter 1 expressed in Xenopus laevis oocytes.  Mol Pharmacol . 1999;  55 847-854
  • 39 Jariyawat S, Sekine T, Takeda M. The interaction and transport of β-lactam antibiotics with the cloned rat renal organic anion transporter 1.  J Pharmacol Exp Ther . 1999;  290 672-677
  • 40 Tsuda M, Sekine T, Takeda M. Transport of ochratoxin A by renal multispecific organic anion transporter 1.  J Pharmacol Exp Ther . 1999;  289 1301-1305
  • 41 Cihler T, Lin D C, Pritchard J B. The antiviral nucleotide analogs cidofovir and adefovir are novel substrates for human and rat renal organic anion transporter 1.  Mol Pharmacol . 1999;  56 570-580
  • 42 Hosoyamada M, Sekine T, Kanai Y. Molecular cloning and functional expression of a multispecific organic anion transporter from human kidney.  Am J Physiol . 1999;  276 F122-F128
  • 43 Sekine T, Cha S H, Tsuda M. Identification of multispecific organic anion transporter 2 expressed predominantly in the liver.  FEBS Lett . 1998;  429 179-182
  • 44 Kusuhara H, Sekine T, Utusnomiya-Tate N. Molecular cloning and characterization of a new multispecific organic anion tansporter from rat brain.  J Biol Chem . 1999;  274 13675-13680
  • 45 Kanai N, Lu R, Satriano J A. Identification and characterization of a prostaglandin tansporter.  Science . 1995;  268 866-869
  • 46 Lu R, Kanai N, Bao Y. Cloning, in vitro expression, and tissue distribution of a human prostaglandin transporter cDNA (hPGT).  J Clin Invest . 1996;  98 1142-1149
  • 47 Schuster V L. Molecular mechanisms of prostaglandin transport.  Annu Rev Physiol . 1998;  60 221-242
  • 48 Kanai N, Lu R, Bao Y. Transient expression of oatp organic anion transporters in mammalian cells: Identification of candidate substrates.  Am J Physiol . 1996;  270 F319-F325
  • 49 Hagenbuch B, Scharschmidt B F, Meier P J. Effect of antisense oligonucleotides on the expression of hepatocellular bile acid and organic anion uptake systems in Xenopus laevis oocytes.  Biochem J . 1996;  316 901-904
  • 50 Kouzuki H, Suzuki H, Ito K. Contribution of sodium taurocholate co-transporting polypeptide to the uptake of its possible substrates into rat hepatocytes.  J Pharmacol Exp Ther . 1998;  286 1043-1050
  • 51 Kouzuki H, Suzuki H, Ito K. Contribution of organic anion transporting polypeptide to uptake of its possible substrates into rat hepatocytes.  J Pharmacol Exp Ther . 1999;  288 627-634
  • 52 de Lennoy I AM, Pang K S. Commentary: Presence of a diffusional barrier on metabolite kinteics: Enalaprilat as a generated versus preformed metabolite.  Drug Metab Dispos . 1986;  14 513-520
  • 53 Schwab A J, Barker III F, Goresky C A. Transfer of enalaprilat across rat liver cell membranes is barrier limited.  Am J Physiol . 1990;  258 G461-G475
  • 54 Yamazaki M, Suzuki H, Hanano M, Sugiyama Y. Na+-independent multispecific anion transporter mediates active transport of pravastatin into rat liver.  Am J Physiol . 1993;  264 G36-G44
  • 55 Yamazaki M, Suzuki H, Sugiyama Y. Recent advances in carrier-mediated hepatic uptake and biliary excretion of xenobiotics.  Pharm Res . 1996;  13 497-513
  • 56 Tokui T, Nakai D, Nakagomi R. Pravastatin, an HMG CoA reductase inhibitor, is transported by rat organic anion transporting polypeptide, oatp2.  Pharm Res . 1999;  16 904-908
  • 57 Vliet A K, van Thiel G CF, Huisman R H. Different effects of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors on steroid synthesis in various human cell types.  Biochim Biophys Acta . 1995;  1254 105-111
  • 58 Tsuji A, Terasaki T, Takanosu K. Uptake of benzylpenicillin, cefpiramide and cefazolin by freshly prepared rat hepatocytes: Evidence for a carrier-mediated transport system.  Biochem Pharmacol . 1986;  35 151-158
  • 59 Sasabe H, Terasaki T, Tsuji A. Carrier-mediated hepatic uptake of quinolone antibiotics in the rat.  J Pharmacol Exp Ther . 1997;  282 162-171
  • 60 Murata M, Tamai I, Sai Y, Tsuji A. Hepatobiliary transport kinetics of HSR-903, a new quinolone antibacterial agent.  Drug Metab Dispos . 1998;  26 1113-1119
  • 61 Kouzuki H, Suzuki H, Sugiyama Y. Pharmacokinetic study of the hepatobiliary transport of indomethacin.  Pharm Res . 2000;  17 432-438
  • 62 Pang K S. Acinar factors in drug processing: Protein binding, futile cycling and cosubstrate.  Drug Metab Rev . 1995;  27 325-368
  • 63 Kwon Y, Morris M E. Membrane transport in hepatic clearance in drugs. II. Zonal distribution patterns of concentration-dependent transport and elimination processes.  Pharm Res . 1997;  14 780-785
  • 64 Dubuisson C, Cresteil D, Desrochers M. Ontogenic expression of the Na+-independent organic anion transoprting polypeptide (oatp) in rat liver and kidney.  J Hepatol . 1996;  25 932-940
  • 65 Stacy N H, Klaassen C D. Uptake of galactose, ouabain and taurocholate into centrilobular and periportal enriched hepatocyte subpopulations.  J Pharmacol Exp Ther . 1981;  216 634-639
  • 66 Stieger B, Hagenbuch B, Landmann L. In situ localization of the hepatocytic Na+/taurocholate cotransporting polypeptide in rat liver.  Gastroenterol . 1994;  107 1781-1787
  • 67 Tan E, Tirona R G, Pang K S. Lack of zonal uptake of estone sulfate in enriched periportal and perivenous isolated rat hepatocytes.  Drug Metab Dispos . 1999;  27 336-341
  • 68 Tirona R G, Tan E, Meier G. Uptake and glutathione conjugation of ethacrynic acid and efflux of the glutathione adduct by periportal and perivenous rat hepatocytes.  J Pharmacol Exp Ther . 1999;  291 1210-1219
  • 69 Milne R W, Jensen R H, Larsen C. Comparison of the disposition of hepatically-generated morphine-3-glucuronide and morphine-6-glucuronide in isolated perfused liver from the guinea pig.  Pharm Res . 1997;  14 1014-1018
  • 70 Takenaka O, Horie T, Suzuki H. Kinetic analysis of hepatobiliary transport of conjugated metabolites in the perfused liver of mutant rats (EHBR) with hereditary conjugated hyperbilirubinemia.  Pharm Res . 1995;  12 1746-1755
  • 71 Takenaka O, Horie T, Suzuki H. Carrier-mediated active transport of the glucuronide and sulfate of 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole (E3040) into rat liver: Quantitative comparison of permeability in isolated hepatocytes, perfused liver and liver in vivo.  J Pharmacol Exp Ther . 1997;  280 948-958
  • 72 Geng W P, Schwab A J, Goresky C A. Carrier-mediated uptake and excretion of bromosulfophthalein-glutathione in perfused rat liver: A multiple indicator dilution study.  Hepatol . 1995;  22 1188-1207
  • 73 Yoshimura T, Shcwab A J, Tao L. Hepatic uptake of hippurate: A multiple-indicator dilution, perfused rat liver study.  Am J Physiol . 1998;  274 G10-G20
  • 74 Garcia C K, Brown M S, Pathak R V. cDNA cloning of MCT2, a second monocarboxylate transporter expressed in different cells than MCT1.  J Biol Chem . 1995;  270 1843-1849
  • 75 de Vries M H, Groothuis G MM, Mulder G J. Excretion of the organic anion harmol sulfate from liver into blood.  Biochem Pharmacol . 1985;  34 2129-2135
  • 76 Hansen A M, Lam D, Chiba M. Uptake of sulfate conjugates by isolated rat hepatocytes.  Drug Metab Dispos . 1996;  24 792-798
  • 77 Hirohashi T, Suzuki H, Ito K. Hepatic expression of multidrug resistance-associated protein-like proteins maintained in Eisai hyperbilirubinemic rats.  Mol Pharmacol . 1998;  53 1068-1075
  • 78 Kiuchi Y, Suzuki H, Hirohashi T. cDNA cloning and inducible expression of human multidrug resistance associated protein 3 (MRP3).  FEBS Lett . 1998;  433 149-152
  • 79 König J, Rost D, Cui Y. Characterization of the human multidrug resistance protein isoform MRP3 localized to the basolateral hepatocyte membrane.  Hepatol . 1999;  29 1156-1163
  • 80 Kool M, van der Linden M, de Haas M. MRP3, an organic anion transporter able to transport anti-cancer drugs.  Proc Natl Acad Sci USA . 1999;  96 6914-6919
  • 81 Suzuki H, Sugiyama Y. Excretion of GSSG and glutathione conjugates mediated by MRP1 and cMOAT/MRP2.  Semin Liver Dis . 1998;  18 359-376
  • 82 König J, Nies A T, Cui Y. Conjugated export pumps of the multidrug resistance protein (MRP) family: Localization, substrate specificity, and MRP2-mediated drug resistance.  Biochim Biophys Acta . 1999;  1461 377-394
  • 83 Hirohashi T, Suzuki H, Sugiyama Y. Characterization of the transport properties of cloned rat multidrug resistance associated protein 3 (MRP3).  J Biol Chem . 1999;  274 15181-15185
  • 84 Hirohashi T, Suzuki H, Takikawa H. ATP-dependent transport of bile salts by rat multidrug resistance-associated protein 3 (MRP3).  J Biol Chem . 2000;  275 2905-2910
  • 85 Eaton D L, Klaassen C D. Carrier-mediated transport of ouabain in isolated hepatocytes.  J Pharmacol Exp Ther . 1978;  205 480-488
  • 86 Steen H, Merema M, Meijer D KF. A multispecific uptake system for taurocholate, cardiac glycosidesw and cationic drugs in the liver.  Biochem Pharmacol . 1992;  44 2323-2331
  • 87 Hedman A, Meijer D KF. The stereoisimers qunine and quinidine exhibit a marked stereoselectivity in the inhibition of hepatobiliary transport of cardiac glycosides.  J Hepatol . 1998;  28 240-249
  • 88 Hedman A, Meijer D KF. Stereoselective inhibition by the diastereomers quinidine and quinine of uptake of cardiac glycosides into isolated rat hepatocytes.  J Pharm Sci . 1998;  87 457-461
  • 89 Bossuyt X, Müller M, Hagenbuch B. Polyspecific drug and steroid clearance by an organic anion transporter of mamalian liver.  J Pharmacol Exp Ther . 1996;  276 891-896
  • 90 Bossuyt X, Müller M, Meier P J. Multispecific amphipathic substrate transport by an organic anion transporter of human liver.  J Hepatol . 1996;  25 733-738
  • 91 van Montfoort J E, Hagenbuch B, Fattinger K E. Polyspecific organic anion transporting polypeptides mediate hepatic uptake of amphipathic type II organic cations.  J Pharmacol Exp Ther . 1999;  291 147-152
  • 92 Koepsell H. Organic cation transporters in intestine, kidney, liver, and brain.  Annu Rev Physiol . 1998;  60 243-266
  • 93 Koepsell H, Gorboulev V, Arndt P. Molecular pharmacology of organic cation tansporters in kidney.  J Membrane Biol . 1999;  167 103-117
  • 94 Zhang L, Brett C M, Giacomini K M. Role of organic cation tranpsorters in drug absorption and elimination.  Annu Rev Pharmacol Toxicol . 1998;  38 431-460
  • 95 Breidert T, Spitzenberger F, Grundemann D. Catecholamine transport by the organic cation transporter type 1 (OCT1).  Br J Pharmacol . 1998;  125 218-224
  • 96 Zhang L, Schaner M E, Giacomini K M. Functional characterization of an organic cation transporter (hOCT1) in a transiently transfected human cell line (HeLa).  J Pharmacol Exp Ther . 1998;  286 354-361
  • 97 Gorboulev V, Ulzheimer J C, Akhoundova A. Cloning and characterization of two human polyspecific organic cation transporters.  DNA Cell Biol . 1997;  16 871-881
  • 98 Zhang L, Dresser M J, Gray A T. Cloning and functional expression of a human liver organic cation transporter.  Mol Pharmacol . 1997;  51 913-921
  • 99 Nakamura H, Sano H, Yamazaki M. Carrier-mediated active transport of histamine H2 receptor antagonists, cimetidine and nizatidine, into isolated rat hepatocytes: Contribution of type I system.  J Pharmacol Exp Ther . 1994;  269 1220-1227
  • 100 Grundemann D, Liebich G, Kiefer N. Selective substrates for non-neuronal monoamine transporters.  Mol Pharmacol . 1999;  56 1-10
  • 101 Yabuuchi H, Tamai I, Nezu J. Novel membrane transporter OCTN1 mediates multispecific, bidirectional, and pH-dependent transport of organic cations.  J Pharmacol Exp Ther . 1999;  289 768-773
  • 102 Nezu J, Tamai I, Oku A. Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter.  Nat Genet . 1999;  21 91-94
  • 103 Tamai I, Ohashi R, Zezu J, Yabuuchi H. Molecular and functional identification of sodium ion-dependent, high affinity human carnitine transporter OCTN2.  J Biol Chem . 1998;  273 20378-20382
  • 104 Ohashi R, Tamai I, Yabuuchi H. Na+-dependent carnitine transport by organic cation transoprter (OCTN2): Its pharmacological and toxicological relevance.  J Pharmacol Exp Ther . 1999;  291 778-784
  • 105 Seth P, Wu X, Huang W. Mutations in novel organic cation transporter (OCTN2), an organic cation / carnitine transporter, with differential effects on the organic cation transport function and the carnitine transport function.  J Biol Chem . 1999;  274 33388-33392
  • 106 Wu X, Huang W, Prasad P D. Functional characteristics and tissue distribution pattern of organic cation transporter 2 (OCTN2), an organic cation / carnitine transporter.  J Pharmacol Exp Ther . 1999;  290 1482-1492
  • 107 Ziegler K, Lins W, Frimmer M. Hepatocellular uptake of cyclosomatostatins: Evidence for a carrier system related to the multispecific bile acid transporter.  Biochim Biophys Acta . 1991;  1061 287-296
  • 108 Terasaki T, Mizukuchi H, Itoho C. Hepatic uptake of octreotide, a long acting somatostain analogue, via a bile acid transport system.  Pharm Res . 1995;  12 11-16
  • 109 Seeberger A, Ziegler K. Hepatocellular uptake of peptides. II. Interaction between hydrophilic linear renin-inhibiting peptides and transport systes for endogenous substrates in liver cells.  Biochem Pharmacol . 1993;  45 917-925
  • 110 Bertrams A, Ziegler A. New substrates of multispecific bile acid transporter in liver cells: Interference of some linear renin inhibiting peptides with transport protein(s) for bile acids.  Biochim Biophys Acta . 1991;  1073 213-220
  • 111 Bertrams A, Ziegler A. Hepatocellular uptake of peptides by bile acid transporters: Relationship of carrier mediated transport of linear peptides with renin inhibiting activity of multispecific bile acid carriers.  Biochim Biophys Acta . 1991;  1091 337-348
  • 112 Ziegler K, Seeberger A. Hepatocellular uptake of peptides I. Carrier-mediated uptake of hydrophilic linear peptides with renin inhibitory activity into isolated rat liver cells.  Biochem Pharmacol . 1993;  45 909-916
  • 113 Gores G J, LaRusso N F, Miller L J. Hepatic processing of cholecystokinin peptides. I. Structural specificity and mechanism of hepatic extraction.  Am J Physiol . 1986;  250 G344-G349
  • 114 Gores G J, Kost L J, Miller L J. Processing of cholecystokinin by isolated liver cells.  Am J Physiol . 1989;  257 G242-G248
  • 115 Ziegler K, Kolac C, Schulze S. Hepatobiliary elimination of certain peptide-mimicing drugs: Linear hydrophobic and hydrophilic renin-inhibitors and hydrophobic cyclopeptides.  J Hepatol . 1996;  24(Suppl 1) 47-52
  • 116 Nakamura T, Hisaka A, Sasaki Y. Carrier mediated active transport of BQ-123, a peptide endothelin antagonist, into rat hepatocytes.  J Pharmacol Exp Ther . 1996;  278 564-572
  • 117 Shin H, Kato Y, Yamada T. Hepatobiliary transport mechanism for the cyclopentapeptide endothelin antagonist BQ-123.  Am J Physiol . 1997;  272 G979-G986
  • 118 Kato Y, Akhteruzzaman S, Hisaka A. Hepatobiliary transport governs overall elimination of peptidic endothelin antagonists in rats.  J Pharmacol Exp Ther . 1999;  288 568-574
  • 119 Akhteruzzaman S, Kato Y, Kouzuki H. Carrier-mediated hepatic uptake of peptidic endothelin antagonists in rats.  J Pharmacol Exp Ther . 1999;  290 1107-1115