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 w as excreted mainly by renal tubular secretion. Plasma clearance was re duced by probenecid from 198 +/- 47 to 119 +/- 41 mL min(-1) (mean +/- S.D.); renal clearance was reduced from 104 +/- 33 to 54 +/- 24 mL mi n(-1) (p < 0.02) by probenecid and to 89 +/- 37 mL min(-1) (NS) by cim etidine. Plasma and urine data were analysed simultaneously with a phy siologically 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 basolate ral 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-bor der exit was found. Estimated inhibition constants of cimetidine and p robenecid were 62 and 4 mu g mL(-1), respectively. Summarizing, raniti dine renal pharmacokinetics were accurately described by the physiolog ically based kidney model presented in this paper. Model calculations suggest that interaction with cimetidine and probenecid results from c ompetition for basolateral ranitidine uptake into tubular cells. (C) 1 998 John Wiley & Sons, Ltd.