A physiologically based kidney model for the renal clearance of ranitidine and the interaction with cimetidine and probenecid in the dog.
Ranitidine renal clearance was investigated in the beagle dog with or without concomitant infusion of cimetidine or probenecid. Ranitidine was excreted mainly by renal tubular secretion. Plasma clearance was reduced by probenecid from 198 +/- 47 to 119 +/- 41 mL min-1 (mean +/- SD.); renal clearance was reduced from 104 +/- 33 to 54 +/- 24 mL min-1 (p < 0.02) by probenecid and to 89 +/- 37 mL min-1 (NS) by cimetidine. Plasma and urine data were analysed simultaneously with a physiologically based kidney model and were both described adequately by the model, although tubular secretion could not be fully characterized as no saturation was achieved despite high dosages. Tubular secretion of ranitidine was simplified to first-order brush-border and basolateral transport across the proximal tubular cell. Basolateral transport was reduced (from 18.4 +/- 7.8 to 13.6 +/- 10.3 min-1 by cimetidine and 3.9 +/- 3.1 min-1 by probenecid), whereas no effect on brush-border exit was found. Estimated inhibition constants of cimetidine and probenecid were 62 and 4 micrograms mL-1, respectively. Summarizing, ranitidine renal pharmacokinetics were accurately described by the physiologically based kidney model presented in this paper. Model calculations suggest that interaction with cimetidine and probenecid results from competition for basolateral ranitidine uptake into tubular cells.
Boom
S P
SP
Department of Pharmacology, University of Nijmegen, The Netherlands.
Meyer
I
I
Wouterse
A C
AC
Russel
F G
FG
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002927:Cimetidine / Q000494:pharmacology*; D004285:Dogs; D004347:Drug Interactions; D006635:Histamine H2 Antagonists / Q000097:blood / Q000652:urine*; D007668:Kidney / Q000378:metabolism*; D007684:Kidney Tubules / Q000378:metabolism; D008297:Male; D008432:Mathematical Computing; D008954:Models, Biological; D011339:Probenecid / Q000494:pharmacology*; D011485:Protein Binding; D011899:Ranitidine / Q000097:blood / Q000652:urine*; D014528:Uricosuric Agents / Q000494:pharmacology*
D001798:Blood Proteins; D006635:Histamine H2 Antagonists; D014528:Uricosuric Agents; D002927:Cimetidine; D011899:Ranitidine; D011339:Probenecid