Renal secretion of the antiviral nucleoside analog AM188 is inhibited by probenecid, p-aminohippuric acid, and cimetidine in the isolated perfused rat kidney

Abstract

Purpose: To investigate the effects of potential inhibitors of membrane transport on the tubular secretion of AM188, an antiviral guanosine analog, in the isolated perfused rat kidney (IPK). Methods: AM188 was administered to the IPK perfusate as a bolus/infusion regimen. In inhibitor groups, probenecid, p-aminohippuric acid (PAH), cimetidine, or nitrobenzylthioinosine was added to the perfusing medium. Results: In control IPKs, the ratio of renal clearance of AM188 (CLR) to GFR was 7.7 ± 0.51 (mean ± SD). The CLR/GFR ratio for AM188 was 6.20 ± 0.41*, 2.85 ± 0.20*, 1.45 ± 0.07*, and 0.80 ± 0.01* when the concentration of probenecid in perfusate was 10, 50, 100, and 1000 M, respectively (*p < 0.05 compared to control group); the ratio was 7.71 ± 0.38, 6.02 ± 0.42*, 1.71 ± 0.15*, and 0.91 ± 0.07* for the PAH group and 6.42 ± 1.70*, 5.33 ± 1.53*, 3.16 ± 0.81*, and 1.21 ± 0.20* for the cimetidine group when the concentrations were 10, 100, 1000 and 10,000 M, respectively; and the ratio was 5.33 ± 0.21* when the concentration of nitrobenzylthioinosine was 5 M. Conclusions: These results suggest that renal tubular secretion of AM188 involves organic anion and cation transport systems.