![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 59, Issue 3, 627-635, March 2001
F. Hoffmann-La Roche Ltd., Pharmaceuticals Division, Non-Clinical
Development Troglitazone is a thiazolidinedione insulin sensitizer drug for the
treatment of type 2 non-insulin-dependent diabetes mellitus (NIDDM).
Based on an increasing number of reports on troglitazone-associated liver toxicity, the cholestatic potential of troglitazone has been
investigated. Rapid and dose-dependent increases in the plasma bile
acid concentrations were observed in rats after a single intravenous
administration of troglitazone. A radiolabeled taurocholic acid tracer
accumulated in liver tissue, indicating an interference with the
hepatobiliary export of bile acids. In isolated canalicular rat liver
plasma membrane preparations, troglitazone competitively inhibited the
ATP-dependent taurocholate transport (apparent
Ki value, 1.3 µM), mediated by the
canalicular bile salt export pump (Bsep). Troglitazone sulfate, the
main troglitazone metabolite eliminated into bile, also showed
competitive Bsep inhibition with an apparent
Ki value of 0.23 µM. A comparable
inhibition was observed for both compounds in canalicular plasma
membrane vesicles prepared from Mrp2-deficient (TR
Drug Safety, Basel, Switzerland
) rats,
suggesting a direct (cis-) inhibition of Bsep by
troglitazone and troglitazone sulfate. A high accumulation potential
was observed for troglitazone sulfate in rat liver tissue, indicating
that the hepatobiliary export of this conjugated metabolite might
represent a rate-limiting step in the overall elimination process of
troglitazone. This accumulation in combination with the high Bsep
inhibition potential suggested that mainly troglitazone sulfate was
responsible for the interaction with the hepatobiliary export of bile
acids at the level of the canalicular Bsep in rats. Such an interaction might lead to a troglitazone-induced intrahepatic cholestasis in humans
as well, contributing to the formation of a troglitazone-induced liver toxicity.
This article has been cited by other articles:
|
|
 |
|
  E. Kis, E. Ioja, T. Nagy, L. Szente, K. Heredi-Szabo, and P. Krajcsi Effect of Membrane Cholesterol on BSEP/Bsep Activity: Species Specificity Studies for Substrates and Inhibitors Drug Metab. Dispos., September 1, 2009; 37(9): 1878 - 1886. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. J. Cui, L. M. Aleksunes, Y. Tanaka, M. J. Goedken, and C. D. Klaassen Compensatory Induction of Liver Efflux Transporters in Response to ANIT-Induced Liver Injury Is Impaired in FXR-Null Mice Toxicol. Sci., July 1, 2009; 110(1): 47 - 60. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. K. Bhargava, B. Joseph, M. Ananthanarayanan, N. Balasubramaniyan, G. G. Tronco, C. J. Palestro, and S. Gupta Adenosine Triphosphate-Binding Cassette Subfamily C Member 2 Is the Major Transporter of the Hepatobiliary Imaging Agent 99mTc-Mebrofenin J. Nucl. Med., July 1, 2009; 50(7): 1140 - 1146. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Zamek-Gliszczynski, K. A. Hoffmaster, K.-i. Nezasa, and K. L. R. Brouwer Apparent Differences in Mechanisms of Harmol Sulfate Biliary Excretion in Mice and Rats Drug Metab. Dispos., November 1, 2008; 36(11): 2156 - 2158. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z.-w. Ye, P. Augustijns, and P. Annaert Cellular Accumulation of Cholyl-Glycylamido-Fluorescein in Sandwich-Cultured Rat Hepatocytes: Kinetic Characterization, Transport Mechanisms, and Effect of Human Immunodeficiency Virus Protease Inhibitors Drug Metab. Dispos., July 1, 2008; 36(7): 1315 - 1321. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Noe, R. Portmann, M.-E. Brun, and C. Funk Substrate-Dependent Drug-Drug Interactions between Gemfibrozil, Fluvastatin and Other Organic Anion-Transporting Peptide (OATP) Substrates on OATP1B1, OATP2B1, and OATP1B3 Drug Metab. Dispos., August 1, 2007; 35(8): 1308 - 1314. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Enokizono, H. Kusuhara, and Y. Sugiyama Regional Expression and Activity of Breast Cancer Resistance Protein (Bcrp/Abcg2) in Mouse Intestine: Overlapping Distribution with Sulfotransferases Drug Metab. Dispos., June 1, 2007; 35(6): 922 - 928. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Enokizono, H. Kusuhara, and Y. Sugiyama Involvement of Breast Cancer Resistance Protein (BCRP/ABCG2) in the Biliary Excretion and Intestinal Efflux of Troglitazone Sulfate, the Major Metabolite of Troglitazone with a Cholestatic Effect Drug Metab. Dispos., February 1, 2007; 35(2): 209 - 214. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Zamek-Gliszczynski, K.-i. Nezasa, X. Tian, J. C. Kalvass, N. J. Patel, T. J. Raub, and K. L. R. Brouwer The Important Role of Bcrp (Abcg2) in the Biliary Excretion of Sulfate and Glucuronide Metabolites of Acetaminophen, 4-Methylumbelliferone, and Harmol in Mice Mol. Pharmacol., December 1, 2006; 70(6): 2127 - 2133. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Mita, H. Suzuki, H. Akita, H. Hayashi, R. Onuki, A. F. Hofmann, and Y. Sugiyama Inhibition of Bile Acid Transport across Na+/Taurocholate Cotransporting Polypeptide (SLC10A1) and Bile Salt Export Pump (ABCB 11)-Coexpressing LLC-PK1 Cells by Cholestasis-Inducing Drugs Drug Metab. Dispos., September 1, 2006; 34(9): 1575 - 1581. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Lang, M. Haberl, D. Jung, A. Drescher, R. Schlagenhaufer, A. Keil, E. Mornhinweg, B. Stieger, G. A. Kullak-Ublick, and R. Kerb Genetic Variability, Haplotype Structures, and Ethnic Diversity of Hepatic Transporters MDR3 (ABCB4) and Bile Salt Export Pump (ABCB11) Drug Metab. Dispos., September 1, 2006; 34(9): 1582 - 1599. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. P. McRae, C. M. Lowe, X. Tian, D. L. Bourdet, R. H. Ho, B. F. Leake, R. B. Kim, K. L. R. Brouwer, and A. D. M. Kashuba Ritonavir, Saquinavir, and Efavirenz, but Not Nevirapine, Inhibit Bile Acid Transport in Human and Rat Hepatocytes J. Pharmacol. Exp. Ther., September 1, 2006; 318(3): 1068 - 1075. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. E. Kostrubsky, S. C. Strom, A. S. Kalgutkar, S. Kulkarni, J. Atherton, R. Mireles, B. Feng, R. Kubik, J. Hanson, E. Urda, et al. Inhibition of Hepatobiliary Transport as a Predictive Method for Clinical Hepatotoxicity of Nefazodone Toxicol. Sci., April 1, 2006; 90(2): 451 - 459. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Zamek-Gliszczynski, K. A. Hoffmaster, X. Tian, R. Zhao, J. W. Polli, J. E. Humphreys, L. O. Webster, A. S. Bridges, J. C. Kalvass, and K. L. R. Brouwer MULTIPLE MECHANISMS ARE INVOLVED IN THE BILIARY EXCRETION OF ACETAMINOPHEN SULFATE IN THE RAT: ROLE OF MRP2 AND BCRP1 Drug Metab. Dispos., August 1, 2005; 33(8): 1158 - 1165. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. C. Kemp, M. J. Zamek-Gliszczynski, and K. L. R. Brouwer Xenobiotics Inhibit Hepatic Uptake and Biliary Excretion of Taurocholate in Rat Hepatocytes Toxicol. Sci., February 1, 2005; 83(2): 207 - 214. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. He, R. E. Talaat, W. F. Pool, M. D. Reily, J. E. Reed, A. J. Bridges, and T. F. Woolf METABOLIC ACTIVATION OF TROGLITAZONE: IDENTIFICATION OF A REACTIVE METABOLITE AND MECHANISMS INVOLVED Drug Metab. Dispos., June 1, 2004; 32(6): 639 - 646. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Nozawa, S. Sugiura, M. Nakajima, A. Goto, T. Yokoi, J.-I. Nezu, A. Tsuji, and I. Tamai INVOLVEMENT OF ORGANIC ANION TRANSPORTING POLYPEPTIDES IN THE TRANSPORT OF TROGLITAZONE SULFATE: IMPLICATIONS FOR UNDERSTANDING TROGLITAZONE HEPATOTOXICITY Drug Metab. Dispos., March 1, 2004; 32(3): 291 - 294. [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]
|
|
|
|
 |
|
 M. Trauner and J. L. Boyer Bile Salt Transporters: Molecular Characterization, Function, and Regulation Physiol Rev, April 1, 2003; 83(2): 633 - 671. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. E. Kostrubsky, M. Vore, E. Kindt, J. Burliegh, K. Rogers, G. Peter, D. Altrogge, and M. W. Sinz The Effect of Troglitazone Biliary Excretion on Metabolite Distribution and Cholestasis in Transporter-Deficient Rats Drug Metab. Dispos., December 1, 2001; 29(12): 1561 - 1566. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. G. Schuetz, S. Strom, K. Yasuda, V. Lecureur, M. Assem, C. Brimer, J. Lamba, R. B. Kim, V. Ramachandran, B. J. Komoroski, et al. Disrupted Bile Acid Homeostasis Reveals an Unexpected Interaction among Nuclear Hormone Receptors, Transporters, and Cytochrome P450 J. Biol. Chem., October 12, 2001; 276(42): 39411 - 39418. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
