Add time:08/06/2019         Source:sciencedirect.com

The effect of the co-infusion of ursodeoxycholate and its taurine conjugate, 3-O-glucuronide and 3,7-disulfate on estradiol-17β-glucuronide-induced cholestasis was examined. Estradiol-17β-glucuronide was intravenously administered to bile-drained rats at a rate of 0.075 μmol/min/100 g for 20 min. Co-infusion of ursodeoxycholate and its conjugates was simultaneously begun at a rate of 0.2 μmol/min/100 g and continued for 120 min. Ursodeoxycholate failed to improve and tauroursodeoxycholate only partially improved estradiol-17β-glucuronide-induced cholestasis between 20 and 40 min, although both bile acids increased bile flow after 80 min. Tauroursodeoxycholate increased biliary estradiol-17β-glucuronide excretion. Ursodeoxycholate-3-O-glucuronide completely inhibited cholestasis induced by estradiol-17β-glucuronide without changing biliary estradiol-17β-glucuronide excretion. Although ursodeoxycholate-3,7-disulfate had only a minor effect on cholestasis, it increased biliary excretion of estradiol-17β-glucuronide. In the Eizai hyperbilirubinuria rat (EHBR), a hyperbilirubinemic mutant Sprague-Dawley rat, the same dose of estradiol-17β-glucuronide failed to induce cholestasis with a marked delay in biliary excretion of estradiol-17β-glcuronide. In summary, ursodeoxycholate-3-O-glucuronide is more effective than tauroursodeoxycholate in inhibiting estradiol-17β-glucuronide-induced cholestasis and ursodoexycholate-3,7-disulfate had little effect. However, the unexpected effects of ursodeoxycholate-3-O-glucuronide and 3,7-disulfate on excretion of estradiol-17β-glucuronide suggest that the interaction of these anions at the canalicular membrane is complicated, with interaction occurring at more than two pathways of the biliary excretion of these anions.

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