Linked Life Data

11557132

Source:http://linkedlifedata.com/resource/pubmed/id/11557132

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pubmed-article:11557132pubmed:abstractTextTroglitazone 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 and its major metabolite troglitazone sulfate has been investigated. In isolated perfused rat livers troglitazone (10 microM) 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 due to the formation rate of troglitazone sulfate, which was four times faster in cytosolic fractions of male rat liver as compared to female rat liver (Clint=132 and 35 microl min(-1) mg(-1), respectively). Troglitazone sulfate strongly inhibited the ATP-dependent taurocholate transport mediated by the canalicular bile salt export pump (Bsep) in isolated canalicular rat liver plasma membrane preparations of both genders (IC(50) value of 0.4-0.6 microM), while troglitazone was 10 times less potent (IC(50) values of 3.9 microM). This high Bsep inhibition potential and the efficient formation and accumulation of troglitazone sulfate in liver tissue, suggested that troglitazone sulfate was mainly 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 potentially also in man to a troglitazone-induced intrahepatic cholestasis, potentially contributing to the formation of troglitazone-induced liver injuries.lld:pubmed
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pubmed-article:11557132pubmed:articleTitleTroglitazone-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.lld:pubmed
pubmed-article:11557132pubmed:affiliationF. Hoffmann-La Roche Ltd., Non-Clinical Development-Drug Safety, PRNS 69/152, 4070 Basel, Switzerland. christoph.funk@roche.comlld:pubmed
pubmed-article:11557132pubmed:publicationTypeJournal Articlelld:pubmed
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