INTERACTION OF 3'-AZIDO-3'-DEOXYTHYMIDINE WITH THE ORGANIC-BASE TRANSPORTER IN A CULTURED RENAL EPITHELIUM

In humans and various animal species, 3'-azido-3'-deoxythymidine (AZT) is in part eliminated by the kidneys, where it undergoes significant tubular secretion. The goal of this project was to develop, in a conti nuous renal epithelial cell line (LLCPK(1)), a model of AZT transport in which mechanisms of drug interactions could be investigated. Transp ort properties of H-3-AZT were studied in LLCPK(1) cells grown as mono layers on permeable filters. This system provides access to the basola teral and apical surfaces of the epithelium and allows the determinati on of substrate transepithelial nux from the basolateral side to the a pical side (B --> A/secretory direction) and apical to basolateral sid e (A --> B/reabsorptive direction). The B --> A flux of AZT was signif icantly greater than B --> A flux of mannitol (a nontransported substr ate) and was temperature dependent (37 degrees C >> 4 degrees C). The AZT A --> B flux was significantly smaller than the B -->, A flux, ind icating that the drug is predominantly secreted in this renal epitheli um. The B --> A flux was significantly inhibited by the organic bases cimetidine, quinine, quinidine, and trimethoprim. Log concentration do se studies indicate that quinine is a weak inhibitor (IC50 = 9.61 mM) of AZT B --> A flux, and that AZT is a moderate inhibitor (IC50 = 0.69 mM) of the organic base cimetidine. These results suggest that AZT ma y share the organic base transporter in the renal epithelium, and that this model can be used successfully to study transport properties and renal drug-drug interactions of AZT.