ABSTRACT
Down-regulation of multidrug resistance protein 2 (Mrp2), a major canalicular organic anion transporter, has been reported in various cholestatic models and in patients with cholestasis. In the present study, biliary excretion of taurolithocholate-sulfate and temocaprilat, substrates of Mrp2, was studied in bile duct-ligated rats and in cholestatic rats induced by ethinylestradiol (EE). Biliary excretion of temocaprilat was more markedly decreased in bile duct-ligated rats than that of taurolithocholate-sulfate. In contrast, biliary excretion of both compounds were similarly inhibited in EE-treated rat. Such difference of the degree of inhibition may have been caused by the different degree of the inhibition of unknown canalicular transporters other than Mrp2 in bile duct-ligated rats.
ABSTRACT
BACKGROUND: Colestimide is a newly developed bile acid-binding resin in Japan, but its bile acid-binding properties have not been studied. METHODS: The absorption of unconjugated bile acids (5 mmol/L) in the ligated rat jejunum was compared in the presence and absence of colestimide. Furthermore, bile acid adsorption by colestimide was also studied in vitro. RESULTS: All bile acids were efficiently absorbed in the jejunum and the cumulative absorption during 120 min was 29-63%. The absorption of chenodeoxycholate, lithocholate, deoxycholate and ursodeoxycholate was dose-dependently inhibited by 2.5 and 5 mg colestimide, whereas the absorption of cholate was not inhibited, even in the presence of 5 mg colestimide. Adsorption of bile acids by colestimide in vitro was approximately 60% for chenodeoxycholate, lithocholate, deoxycholate and ursodeoxycholate, whereas the adsorption of cholate was low (16%). CONCLUSIONS: Jejunal absorption of ursodeoxycholate was inhibited by colestimide to a similar extent as other dihydroxy bile acids, whereas that of cholate was not inhibited under the same conditions.
