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Titolo:
Troglitazone-induced intrahepatic cholestasis by an interference with the hepatobiliary export of bile acids in male and female rats. Correlation with the gender difference in troglitazone sulfate formation and the inhibition of the canalicular bile salt export pump (Bsep) by troglitazone and troglitazone sulfate
Autore:
Funk, C; Pantze, M; Jehle, L; Ponelle, C; Scheuermann, G; Lazendic, M; Gasser, R;
Indirizzi:
F Hoffmann La Roche & Co Ltd, Nonclin Dev Drug Safety, CH-4070 Basel, Switzerland F Hoffmann La Roche & Co Ltd Basel Switzerland CH-4070 asel, Switzerland
Titolo Testata:
TOXICOLOGY
fascicolo: 1, volume: 167, anno: 2001,
pagine: 83 - 98
SICI:
0300-483X(20011005)167:1<83:TICBAI>2.0.ZU;2-D
Fonte:
ISI
Lingua:
ENG
Soggetto:
PLASMA-MEMBRANE VESICLES; ANTIDIABETIC AGENT; HUMAN LIVER; NAK-ATPASE; TRANSPORT; MECHANISMS; HEPATOTOXICITY; PHARMACOKINETICS; DISPOSITION; EXPRESSION;
Keywords:
cholestasis; troglitazone; bile acids; ABC transporter; hepatotoxicity; sulfotransferase; drug-drug interactions;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
44
Recensione:
Indirizzi per estratti:
Indirizzo: Funk, C F Hoffmann La Roche & Co Ltd, Nonclin Dev Drug Safety, PRNS 69-152, CH-4070 Basel, Switzerland F Hoffmann La Roche & Co Ltd PRNS 69-152 Basel Switzerland CH-4070
Citazione:
C. Funk et al., "Troglitazone-induced intrahepatic cholestasis by an interference with the hepatobiliary export of bile acids in male and female rats. Correlation with the gender difference in troglitazone sulfate formation and the inhibition of the canalicular bile salt export pump (Bsep) by troglitazone and troglitazone sulfate", TOXICOLOGY, 167(1), 2001, pp. 83-98

Abstract

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, thecholestatic potential of troglitazone and its major metabolite troglitazone sulfate has been investigated. In isolated perfused rat livers troglitazone (10 muM) reduced the bile flow by 25% (female) to 50% (male) within 60 min. After single intravenous administrations of troglitazone to rats of both genders, rapid and dose-dependent increases in the plasma bile acid concentrations were observed, with male rats being more sensitive than female rats. In male rat liver tissue fivefold higher troglitazone sulfate levels were measured as compared to female rat liver tissue. This difference was dueto the formation rate of troglitazone sulfate, which was four times fasterin cytosolic fractions of male rat liver as compared to female rat liver (Clint = 132 and 35 mul min(-1) mg(-1), respectively). Troglitazone sulfate strongly inhibited the ATP-dependent taurocholate transport mediated by thecanalicular bile salt export pump (Bsep) in isolated canalicular rat liverplasma membrane preparations of both genders (IC50 value of 0.4-0.6 muM), while troglitazone was 10 times less potent (IC50 values of 3.9 muM). This high Bsep inhibition potential and the efficient formation and accumulationof troglitazone sulfate in liver tissue, suggested that troglitazone sulfate was mainly responsible for the interaction with the hepatobiliary exportof bile acids at the level of the canalicular Bsep in rats. Such an interaction might lead potentially also in man to a troglitazone-induced intrahepatic cholestasis, potentially contributing to the formation of troglitazone-induced liver injuries. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 04/04/20 alle ore 14:41:30