CHARACTERIZATION OF AND THE INFLUENCE OF CALCIUM-CHANNEL BLOCKERS ON THE RENAL EXCRETION OF PYRIMIDINE ANTICANCER AGENTS

The renal handling of two anticancer (a-Ca) pyrimidines 5-fluorodeoxyu ridine (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. B ased on the FUdR:inulin clearance ratio and 5-FU:inulin clearance rati o, it was determined that FUdR was secreted into renal tubules while 5 -FU underwent reabsorption. The secretion of FUdR was inhibited by cim etidine and dipyridamole but not by probenecid or phloridzin. While th e clearance ratio of 5FU:inulin was significantly reduced by phloridzi n, 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 a lso examined. VER increased the secretion of FUdR without affecting th e reabsorption of 5-FU while DZM slightly decreased the secretion of F UdR and prevented the reabsorption of 5-FU. These data suggest that th e organic cation carrier and a dipyridamole-sensitive nucleoside trans porter are involved in the renal excretion of FUdR; that the renal tra nsport of both FUdR and 5-FU is associated with the calcium channel; a nd that 5-FU utilizes, at least in part, the glucose transporter for i ts reabsorption.