Watt J A, Dickinson R G
Department of Medicine, University of Queensland, Royal Brisbane Hospital, Australia.
Biochem Pharmacol. 1990 Mar 15;39(6):1067-75. doi: 10.1016/0006-2952(90)90286-t.
Diflunisal acyl glucuronide (DAG) is a major metabolite of diflunisal (DF) in rats and humans. We have investigated the reactivity of DAG, in purified albumin solutions and plasma from both rat and human sources, along three interrelated pathways: rearrangement via acyl migration to yield positional isomers of DAG, hydrolysis of DAG and/or its isomers to liberate DF, and formation of covalent adducts of DF (via DAG and/or its isomers) with plasma protein. Two initial concentrations of DAG (ca. 50 and 10 micrograms DF equivalents/mL) were used throughout. In all incubations, the order of quantitative importance of the reactions was: rearrangement greater than hydrolysis greater than covalent binding. At pH 7.4 and 37 degrees, degradation of DAG in albumin solutions (e.g. half-life ca. 95 min in fatty acid-free human serum albumin) was retarded in comparison to that found in buffer alone (half-life ca. 35 min). Degradation in unbuffered rat and human plasma containing heparin was comparable to that found in buffer. Maximal covalent binding to protein was achieved after 4-8 hr incubation, and was greatest for fatty acid-free human serum albumin (165 ng DF/mg albumin). Thereafter, slow degradation of the adducts was observed. Formation of DF-plasma protein adducts in vivo was also found in rats and humans dosed with DF.
双氟尼酸酰基葡萄糖醛酸苷（DAG）是双氟尼酸（DF）在大鼠和人体内的主要代谢产物。我们研究了DAG在大鼠和人源的纯化白蛋白溶液及血浆中的反应活性，涉及三条相互关联的途径：通过酰基迁移重排生成DAG的位置异构体、DAG及其异构体水解以释放DF，以及DF（通过DAG和/或其异构体）与血浆蛋白形成共价加合物。整个实验使用了两种初始浓度的DAG（约50和10微克DF当量/毫升）。在所有孵育实验中，反应在数量上的重要性顺序为：重排大于水解大于共价结合。在pH 7.4和37℃条件下，与单独缓冲液中的情况（半衰期约35分钟）相比，白蛋白溶液中DAG的降解（例如在无脂肪酸的人血清白蛋白中半衰期约95分钟）受到抑制。含肝素的未缓冲大鼠和人血浆中的降解情况与缓冲液中的相当。与蛋白质的最大共价结合在孵育4 - 8小时后达到，且对无脂肪酸的人血清白蛋白而言最大（165纳克DF/毫克白蛋白）。此后，观察到加合物的缓慢降解。在给予DF的大鼠和人体内也发现了体内DF - 血浆蛋白加合物的形成。
