Effect of experimental diabetes on elimination kinetics of diflunisal in rats.
The effects of insulin-deficient diabetes on the elimination of diflunisal were investigated in streptozotocin-treated rats. Diflunisal, a fluorinated salicylate with nonsteroidal antiinflammatory properties, is eliminated primarily as the ester and ether glucuronides. After an iv injection of a 10 mg/kg dose, diabetic rats cleared diflunisal more rapidly than control rats; time-averaged total body clearances were 1.96 +/- 0.29 and 1.10 +/- 0.12 ml/min/kg, respectively. For a low clearance drug such as diflunisal, changes in the total body clearance can result from changes in the extent of plasma protein binding and/or drug metabolic rate. To determine whether the pronounced changes in elimination clearance in diabetic rats were due to the changes in plasma protein binding or enzyme activity, diflunisal was infused to obtain steady state kinetics. At steady state, the unbound intrinsic clearance increased from 43.4 +/- 16.4 ml/min/kg in the control rats to 82.5 +/- 21.1 ml/min/kg in diabetic rats at a high infusion rate (72 micrograms/min). When the infusion rate was lowered to 4.5 micrograms/min, the respective values for the unbound intrinsic clearance were 353 +/- 101 ml/min/kg and 561 +/- 112 ml/min/kg. Diabetic rats, however, showed no changes in plasma protein binding of diflunisal. The data suggest that the elimination of diflunisal was increased as a result of increased enzyme activity. Insulin treatment appeared to reverse the diabetic effect, suggesting that the effect on drug metabolism was the result of insulin deficiency and not a secondary or nonspecific effect of streptozotocin.(ABSTRACT TRUNCATED AT 250 WORDS)
Lin
J H
JH
Merck Sharp & Dohme Research Laboratories, West Point, PA 19486.
DeLuna
F A
FA
Tocco
D J
DJ
Ulm
E H
EH
D000818:Animals; D001646:Bile / Q000032:analysis; D001798:Blood Proteins / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004061:Diflunisal / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D005965:Glucuronates / Q000378:metabolism; D008297:Male; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains; D012459:Salicylates / Q000493:pharmacokinetics*; D013997:Time Factors
D001798:Blood Proteins; D005965:Glucuronates; D012459:Salicylates; D004061:Diflunisal