Intestinal Absorption Mechanisms of Mizoribine without Sodium Intake

Abstract

An immunosuppressant, mizoribine, is absorbed in the intestine via Na⁺-coupled concentrative nucleoside transporter (CNT). However, our previous clinical research indicated that orally administered mizoribine is absorbed well even under fasting condition. In the present study, we investigated the intestinal absorption mechanisms of mizoribine without sodium intake. We evaluated the extent of mizoribine intestinal absorption and the sodium concentration in intestinal lumen in rats using an in situ closed loop method. In addition, we evaluated the secretion mechanisms of sodium into intestinal lumen. The absorption of mizoribine in the absence of sodium administration decreased slightly as compared with the absorption in the presence of sodium administration. Nitrobenzylmercaptoprine ribonucleoside, which is an inhibitor of sodium independent equilibrative nucleoside transporter (ENT), significantly reduced the absorption of mizoribine in the absence of sodium administration. The sodium concentration in the intestinal lumen increased rapidly up to 120 mM. Amiloride did not affect the sodium concentration in the intestinal lumen. Therefore, sodium/proton exchanger was unlikely to contribute to the secretion of sodium into the intestinal lumen. These findings suggest that sodium is secreted rapidly into the intestinal lumen, and that CNT and ENT function cooperatively on the intestinal absorption of mizoribine even without sodium intake.