Increased intestinal absorption of mizoribine, an immunosuppressive agent, in cholestatic rats

The intestinal absorption of mizoribine, an imidazole nucleoside, is mediated by concentrative nucleoside transporter (CNT)1 and CNT2 in rat. Previously, bile and bile salts such as sodium glycocholate were found to suppress the intestinal absorption of mizoribine. In the present study, the contribution of bile on the intestinal absorption of mizoribine was further evaluated in rats. Cholestatic states were induced by an intraperitoneal injection (2 ml/kg) of 50% carbon tetrachloride (CCl4) dissolved in olive oil, or oral administration (100 mg/2 ml/kg) of alpha-naphthylisothiocyanate (ANIT) dissolved in olive oil. The animals were subjected to absorption studies 24 h after treatment. Cholestatic states were confirmed by measuring plasma concentrations of bile acids and bile flow rates. When oral bioavailability of mizoribine was estimated by the recovery amount in the urine, rats under cholestatic states exhibited significantly higher oral bioavailabilities than untreated control rats. In contrast, the intestinal absorption percentages of mizoribine from in-situ lavaged intestinal loops were the same magnitudes among untreated control, CCl4- and ANIT-treated rats. These results indicated that the increased oral bioavailability of mizoribine in cholestatic rats was not ascribed to the modulation of nucleoside transporter's expression. In conclusion, various diseased states accompanied with cholestasis may increase the oral bioavailability of mizoribine, possibly due to its less amounts of bile in the intestinal lumen.