EFFECT OF CATIONIC DRUGS ON THE RENAL SECRETION OF RANITIDINE IN THE RAT ISOLATED-PERFUSED KIDNEY

1. The rat isolated perfused kidney (IPK) was used to determine whethe r the renal tubular secretion of ranitidine is influenced by clinicall y relevant concentrations of other organic cationic drugs (amantadine, pseudoephedrine, triamterene and trimethoprim) that also undergo tubu lar secretion, 2, Ranitidine and [H-3]-ranitidine were administered to the recirculating perfusion medium as a loading dose followed by a co nstant infusion to maintain clinically relevant perfusate ranitidine c oncentrations in the range 400-700 ng/mL. The renal clearance of ranit idine (CLR) was calculated, as was glomerular filtration rate (GFR), f rom the renal clearance of [C-14]-inulin, 3, A total of 20 perfusions were performed and, in each case, ranitidine was administered for 80 m in, In four control IPK, no drug other than ranitidine was administere d, In the remaining IPK, amantadine, pseudoephedrine, triamterene or t rimethoprim (it = 4 in each case) were administered to achieve low med ium and high concentrations during the 20-40, 40-60 and 60-80 min peri ods, respectively, 4, The mean (+/-SD) unbound fraction of ranitidine in the perfusion medium was 0.889+/-0.046 and was not altered (P>0.05) by the presence of the other drugs, 5. The CLR/GFR ratio for ranitidi ne in all kidneys was substantially greater than unity and had a mean value of 10.65 or greater in control kidneys, indicating extensive net tubular secretion, 6, The CLR/GFR was not affected (P>0.05) by amanta dine, pseudoephedrine or triamterene at any concentration or by trimet hoprim at the low concentration, However, medium (2000 ng/mL) and high (5000 ng/mL) concentrations of trimethoprim caused significant reduct ions in CLR/GFR of 20 and 28%, respectively (P<0.05), 7, The results i ndicate that at clinically relevant concentrations the renal tubular s ecretion of ranitidine is inhibited by trimethoprim, but not by amanta dine, pseudoephedrine or triamterene.