Study on intestinal absorption sites of mizoribine and ribavirin, substrates for concentrative nucleoside transporter(s), in rats

The absorption sites of mizoribine (an imidazole nucleoside) and ribavirin (a purine nucleoside) in the small intestine were evaluated in rats. The intestinal absorption of mizoribine is known to be mediated by rat concentrative nucleoside transporter (CNT)1 and CNT2. In contrast, the absorption mechanism of ribavirin in rats is not yet fully understood. Thus, the intestinal absorption of ribavirin was characterized firstly. In in-situ jejunum loop studies, the absorption percentage of ribavirin at a dose of 25 mg/kg was significantly lower than those after 1 mg/kg and 5 mg/kg doses. Coadministration of adenosine, inosine and mizoribine, but not thymidine and gemcitabine, significantly suppressed the intestinal absorption of ribavirin, indicating that ribavirin absorption is mediated by CNT2 in rats. In in-situ loop studies, mizoribine and ribavirin were absorbed to the same extents both in the proximal and distal small intestine. In vivo study was carried out using mizoribine, in which the gastric emptying rates altered by a subcutaneous injection of metoclopramide or scopolamine butylbromide exerted no significant effects on the values of peak plasma level (Cmax), area under the plasma concentration–time profile from 0 to 6 h (AUC0–6), and urinary excretion percentage of mizoribine given orally, though the time to reach Cmax (Tmax) of mizoribine was altered by each treatment. In conclusion, mizoribine and ribavirin were found to be absorbed efficiently to the same extents from the whole small intestine. Also, the altered gastric emptying rates exerted no significant effects on the oral bioavailabilities of mizoribine and ribavirin.