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The aim of the present study was to evaluate the mechanisms responsible for our previous finding that the uptake of mizoribine by human intestinal epithelial LS 180 cells is considerably lower than that of the structurally-related compound ribavirin.We confirmed that the uptake of 400μM mizoribine by the cells in 30 min was significantly lower than that of 400μM ribavirin.In addition,the steady-state cell/medium (C/M) ratio for mizoribine under low (1 mM) extracellular Na+ conditions was far below 1.0 (approximately 0.1),whereas that of ribavirin was approximately 0.6.Furthermore,the steadystate C/M ratio of mizoribine under high (126 mM) extracellular Na+ conditions was still much lower than 1.0 (approximately 0.2),whereas that of ribavirin was higher than 1.0 (approximately 1.4).These findings indicate that the transport activity of the unidentified efflux transporter for mizoribine (but not ribavirin) in LS 180 cells is much higher than that of the Na+-independent (equilibrative) and/or Na+-coupled (active) uptake nucleoside transporters under the experimental conditions used,and that the relatively higher affinity of mizoribine for the efflux transporter is at least partly responsible for its lower uptake.

Mechanisms Responsible for Different Rates of Uptake of Mizoribine and Ribavirin by Human Epithelial LS 180 Cells