Smith P C, McDonagh A F, Benet L Z
Department of Pharmacy, School of Pharmacy, University of California, San Francisco.
J Pharmacol Exp Ther. 1990 Jan;252(1):218-24.
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.
在兔子和豚鼠中研究了佐美酸（Z）及其酰基葡萄糖醛酸代谢物的处置情况，以确定组织酯酶对佐美酸葡萄糖醛酸（ZG）的水解是否在体内发生，以及酯酶抑制对ZG暴露及随后与血浆蛋白共价结合会产生何种影响。ZG在豚鼠和兔子体内均迅速被水解，释放出Z。通过在给麻醉的、胆管结扎的豚鼠静脉注射Z或ZG的同时给予苯甲基磺酰氟（PMSF），来确定组织酯酶抑制的作用。给予PMSF使ZG的表观血浆清除率降低了86%，并使Z的表观血浆清除率提高了300%。PMSF处理显著增加了豚鼠通过血浆浓度-时间曲线下面积（AUC）测得的对ZG的暴露。Z与豚鼠血浆蛋白的共价结合与ZG的AUC密切相关，但与Z的AUC无关。豚鼠中Z共价结合与ZG的AUC之间的相关性与在人类中发现的相似，这表明从动物研究中可能可以预测酰基葡萄糖醛酸在人类中与蛋白质形成共价加合物的程度。
