The effect of experimental renal failure on tolfenamic acid disposition in the dog

The pharmacokinetic disposition of tolfenamic acid, an NSAID, after a single administration of tolfenamic acid (4 mg kg(-1)) by the intravenous (IV) route was compared in eight dogs before and after a surgically induced renal failure. Renal impairment was confirmed by a significant increase (p <0.001) of water intake, urine volume, and urea and creatinine plasma concentration. PAH and inulin clearances decreased after surgery from 15.2 +/- 4.2 to 9.5 +/- 0.8 mL kg(-1) min(-1) (p < 0.05) and from 4.37 +/- 1.15 to 2.43 +/- 0.88 mL kg(-1) min(-1) (p=0.067),respectively. After surgery, clearance of TA was significantly (p <0.001) increased, from 2.22 +/- 1.68 to 3.59 +/- 1.81 mL kg (-1) min(-1). There was no modification of the steady-state volume of distribution (p > 0.05) and the mean residence time was significantly decreased from 606 +/- 199 to 373 +/- 302 min (p < 0.05). No variation of binding to plasma proteins (> or = 99%) was observed. These results suggest that renal insufficiency could increase hepatic metabolism and/or alter the enterohepatic cycle of TA.