EFFECTS OF PROBENECID AND CIMETIDINE ON THE RENAL EXCRETION OF 3'-AZIDO-3'-DEOXYTHYMIDINE IN RATS

The mechanisms underlying the inhibitory effects exerted by probenecid and cimetidine on the renal excretion of 3'-azido-3'-deoxythymidine ( AZT) were investigated in rats in vivo. On i.v. administration, the fi ndings indicated that both probenecid and cimetidine increased the pla sma concentration of AZT and inhibited its renal excretion. To clarify the mechanisms underlying the interaction of these drugs with AZT and to elucidate the process of renal secretion of AZT, further investiga tion was performed, in which [H-3]AZT (0.5 mu M) was injected rapidly into the right renal artery, and its outflow profile from the right ur eter was compared with that from the left ureter. In control experimen ts, 56.6% of the administered AZT was secreted from the right kidney, and it was calculated that the transcellular transit time of AZT in th is process was 0.30 min. In the presence of 10 mM probenecid and of 10 mM cimetidine, the secretion of AZT was reduced to 15.3 and 32.3%, re spectively, the inhibition induced by probenecid being more effective than that induced by cimetidine. However, the transcellular transit ti me of AZT increased to 0.53 and 1.21 min in the probenecid and cimetid ine studies, respectively. Thus, cimetidine was more potent than probe necid in its effects on the transit time. These findings indicate that probenecid and cimetidine affect different steps in the renal secreti on of AZT. It was therefore concluded that, on the renal plasma membra ne, AZT is transported by anion transport systems, whereas on the brus h border membrane, AZT is secreted by cation transport systems.