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 whether the renal tubular secretion of ranitidine is influenced by clinically relevant concentrations of other organic cationic drugs (amantadine, pseudoephedrine, triamterene and trimethoprim) that also undergo tubular secretion. 2. Ranitidine and [3H]-ranitidine were administered to the recirculating perfusion medium as a loading dose followed by a constant infusion to maintain clinically relevant perfusate ranitidine concentrations in the range 400-700 ng/mL. The renal clearance of ranitidine (CL[R]) was calculated, as was glomerular filtration rate (GFR), from the renal clearance of [14C]-inulin. 3. A total of 20 perfusions were performed and, in each case, ranitidine was administered for 80 min. In four control IPK, no drug other than ranitidine was administered. In the remaining IPK, amantadine, pseudoephedrine, triamterene or trimethoprim (n = 4 in each case) were administered to achieve low, medium and high concentrations during the 20-40, 40-60 and 60-80 min periods, 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 CL(R)/GFR ratio for ranitidine 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 CL(R)/GFR was not affected (P>0.05) by amantadine, pseudoephedrine or triamterene at any concentration or by trimethoprim at the low concentration. However, medium (2000 ng/mL) and high (5000 ng/mL) concentrations of trimethoprim caused significant reductions in CL(R)/GFR of 20 and 28%, respectively (P<0.05). 7. The results indicate that at clinically relevant concentrations the renal tubular secretion of ranitidine is inhibited by trimethoprim, but not by amantadine, pseudoephedrine or triamterene.
Nation
R L
RL
Centre for Pharmaceutical Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide. roger.nation@unisa.edu.au
Evans
A M
AM
Cabot
J L
JL
Shanahan
K M
KM
Hsyu
P H
PH
D000547:Amantadine / Q000494:pharmacology; D000818:Animals; D002412:Cations; D004809:Ephedrine / Q000494:pharmacology; D066298:In Vitro Techniques; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D010477:Perfusion; D011485:Protein Binding / Q000187:drug effects; D011899:Ranitidine / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014223:Triamterene / Q000494:pharmacology; D014295:Trimethoprim / Q000494:pharmacology
D002412:Cations; D011899:Ranitidine; D014295:Trimethoprim; D000547:Amantadine; D004809:Ephedrine; D014223:Triamterene