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 intraven ous (IV) route was compared in eight dogs before and after a surgicall y induced renal failure. Renal impairment was confirmed by a significa nt increase (p<0.001) of water intake, urine volume, and urea and crea tinine 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 f rom 4.37+/-1.15 to 2.43+/-0.88 mL kg(-1) min(-1) (p=0.067), respective ly. After surgery, clearance of TA was significantly (p<0.001) increas ed, from 2.22+/-1.68 to 3.59+/-1.81 mL kg(-1) min(-1). There was no mo dification 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 (great er than or equal to 99%) was observed. These results suggest that rena l insufficiency could increase hepatic metabolism and/or alter the ent erohepatic cycle of TA.