Renal secretion of the antiviral nucleoside analog AM188 is inhibited by probenecid, p-aminohippuric acid, and cimetidine in the isolated perfused rat kidney.
OBJECTIVE
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.
Wang
Jiping
J
Centre for Pharmaceutical Research, School of Pharmacy and Medical Sciences, University of South Australia, North Terrace, Adelaide, SA 5000, Australia.
Nation
Roger L
RL
Evans
Allan M
AM
Cox
Susan
S
D000818:Animals; D000998:Antiviral Agents / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000493:pharmacokinetics; D002927:Cimetidine / Q000494:pharmacology*; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology; D006151:Guanosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000493:pharmacokinetics; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D009399:Nephrons / Q000187:drug effects* / Q000378:metabolism*; D010477:Perfusion / Q000379:methods; D011339:Probenecid / Q000494:pharmacology*; D051381:Rats; D013868:Thioinosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014018:Tissue Distribution / Q000187:drug effects; D010130:p-Aminohippuric Acid / Q000494:pharmacology*
C490816:9-(3-hydroxy-2-hydroxymethylprop-1-yl)-guanine; D000998:Antiviral Agents; D006151:Guanosine; D013868:Thioinosine; D002927:Cimetidine; C001789:4-nitrobenzylthioinosine; D011339:Probenecid; D010130:p-Aminohippuric Acid