McKinnon G E, Dickinson R G
Department of Medicine, University of Queensland, Royal Brisbane Hospital, Australia.
Res Commun Chem Pathol Pharmacol. 1989 Dec;66(3):339-54.
Acyl glucuronide conjugates of carboxylic drugs have been shown over the past decade to be potentially reactive metabolites, undergoing hydrolysis, intramolecular rearrangement and intermolecular transacylation reactions. The present report describes the covalent binding of diflunisal (D) and probenecid (P) to plasma protein of five healthy volunteers who took a 6-day course of oral D with oral P co-administered during the last 2 days. Maximum concentrations of the D- and P-adducts were achieved within one day of cessation of dosing, and were 35 +/- SE 1 and 17 +/- SE 1 ng/mg protein respectively. The D-protein adduct was eliminated from plasma in a biphasic manner, with a terminal half-life of 10.0 +/- SE 0.9 days. In contrast, elimination of the P-protein adduct was monophasic with a half-life of 13.5 +/- SE 0.3 days. The adducts were still measurable in plasma at least one month after the parent reversibly-bound drugs were undetectable. It is not known whether such covalent binding of the drugs, presumably via their acyl glucuronides, could have any biological consequences, such as induction of hypersensitivity reactions.
在过去十年中，羧酸类药物的酰基葡糖醛酸共轭物已被证明是潜在的活性代谢物，会发生水解、分子内重排和分子间转酰基反应。本报告描述了双氯芬酸（D）和丙磺舒（P）与五名健康志愿者血浆蛋白的共价结合情况，这些志愿者接受了为期6天的口服D疗程，并在最后2天同时口服P。在停药后一天内达到D-和P-加合物的最大浓度，分别为35±标准误1和17±标准误1 ng/mg蛋白。D-蛋白加合物以双相方式从血浆中消除，终末半衰期为10.0±标准误0.9天。相比之下，P-蛋白加合物的消除是单相的，半衰期为13.5±标准误0.3天。在母体可逆结合药物无法检测到后至少一个月，血浆中仍可检测到加合物。尚不清楚药物的这种共价结合（推测是通过其酰基葡糖醛酸）是否会产生任何生物学后果，例如诱导过敏反应。
