Spa. Boom et al., A PHYSIOLOGICALLY-BASED KIDNEY MODEL FOR THE RENAL CLEARANCE OF RANITIDINE AND THE INTERACTION WITH CIMETIDINE AND PROBENECID IN THE DOG, Biopharmaceutics & drug disposition, 19(3), 1998, pp. 199-208
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.