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*TOLMETIN

Effect of esterase inhibition on the disposition of zomepirac glucuronide and its covalent binding to plasma proteins in the guinea pig

PC Smith, AF McDonagh and LZ Benet

Department of Pharmacy, School of Pharmacy, University of California, San Francisco.

The disposition of zomepirac (Z) and its acyl glucuronide metabolite were studied in rabbits and guinea pigs to determine if hydrolysis of zomepirac glucuronide (ZG) by tissue esterases occurs in vivo and what effect inhibition of esterases would have on exposure to ZG and subsequent covalent binding to plasma proteins. ZG was hydrolyzed rapidly in vivo by both guinea pigs and rabbits, liberating Z. The effect of inhibition of tissue esterases was determined by administration of phenylmethylsulfonyl fluoride (PMSF) concurrently with i.v. doses of Z or ZG to anesthetized, bile duct ligated guinea pigs. Administration of PMSF decreased the apparent plasma clearance of ZG by 86% and elevated the apparent plasma clearance of Z by 300%. Exposure of the guinea pigs to ZG as measured by the area under the plasma concentration vs. time curve (AUC) was increased substantially by PMSF treatment. Covalent binding of Z to plasma proteins in the guinea pig correlated well with AUC of ZG, but not with AUC of Z. The correlation of Z covalent binding with AUC of ZG in the guinea pig is similar to that found in humans suggesting that the degree to which acyl glucuronides form covalent adducts with proteins in humans may be predictable from studies in animals.

Volume 252, Issue 1, pp. 218-224, 01/01/1990
Copyright © 1990 by American Society for Pharmacology and Experimental Therapeutics




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Copyright © 1990 by the American Society for Pharmacology and Experimental Therapeutics.