Characterization of and the influence of calcium channel blockers on the renal excretion of pyrimidine anticancer agents.

Abstract

The renal handling of two anticancer (a-Ca) pyrimidines 5-fluorodeoxyuridine (FUdR) and 5-fluorouracil (5-FU) was investigated in clearance experiments in CF-1 mice using specific inhibitors of classical renal transport systems. The 5-FU was derived from the metabolism of FUdR. Based on the FUdR:inulin clearance ratio and 5-FU:inulin clearance ratio, it was determined that FUdR was secreted into renal tubules while 5-FU underwent reabsorption. The secretion of FUdR was inhibited by cimetidine and dipyridamole but not by probenecid or phloridzin. While the clearance ratio of 5-FU:inulin was significantly reduced by phloridzin, it (i.e., the ratio) was not affected by cimetidine, dipyridamole, or probenecid. The impact of two calcium channel blockers, diltiazem (DZM) and verapamil (VER), on the renal handling of FUdR and 5-FU was also examined. VER increased the secretion of FUdR without affecting the reabsorption of 5-FU while DZM slightly decreased the secretion of FUdR and prevented the reabsorption of 5-FU. These data suggest that the organic cation carrier and a dipyridamole-sensitive nucleoside transporter are involved in the renal excretion of FUdR; that the renal transport of both FUdR and 5-FU is associated with the calcium channel; and that 5-FU utilizes, at least in part, the glucose transporter for its reabsorption.