Effects of Dipyridamole Coadministration on the Pharmacokinetics of Ribavirin in Healthy Volunteers

Abstract

Ribavirin (RBV), a guanosine analog for treatment of hepatitis C, is a substrate of a nucleoside transporter, solute carrier family 29 member 1 (SLC29A1). To clarify the impact of SLC29A1 on the pharmacokinetics of RBV, an open-label, crossover study of single-dose RBV (200 mg, p.o.) with and without coadministration of dipyridamole (DP), an inhibitor of SLC29A1, was performed. Plasma and erythrocyte concentrations of RBV in the control phase and DP phase (25 mg, 3 times daily for 4 days) were compared in 10 healthy volunteers. SLC29A1 mRNA expression in peripheral blood mononuclear cells was also determined. In the DP phase, area under the concentration-time curves (AUC) of RBV in plasma and erythrocytes showed reductions of 23% and 17%, respectively (p < 0.05), with increases in apparent oral clearance of 18% and 25%, respectively (p < 0.05). The reduction rate of the AUC of erythrocyte RBV in the DP phase was associated with SLC29A1 mRNA expression: higher mRNA expression showed greater AUC reduction. The elimination half-life of both plasma and erythrocyte RBV did not differ between the 2 phases. These results suggest that RBV/DP coadministration reduces the concentration of RBV in blood by inhibiting an important role of SLC29A1 in gastrointestinal absorption of RBV.