Jiping Wang1, Roger L Nation, Allan M Evans, Susan Cox. 1. Centre for Pharmaceutical Research, School of Pharmacy and Medical Sciences, University of South Australia, North Terrace, Adelaide, SA 5000, Australia.
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 CL(R)/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 microM, 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 microM, respectively; and the ratio was 5.33 +/- 0.21* when the concentration of nitrobenzylthioinosine was 5 microM. CONCLUSIONS: These results suggest that renal tubular secretion of AM188 involves organic anion and cation transport systems.
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 CL(R)/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 microM, 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 microM, respectively; and the ratio was 5.33 +/- 0.21* when the concentration of nitrobenzylthioinosine was 5 microM. CONCLUSIONS: These results suggest that renal tubular secretion of AM188 involves organic anion and cation transport systems.