Smith P C, McDonagh A F, Benet L Z
J Clin Invest. 1986 Mar;77(3):934-9. doi: 10.1172/JCI112392.
Zomepirac is a nonsteroidal anti-inflammatory drug recently withdrawn from use because of an unexplained high incidence of immunological reactions. It is metabolized in humans to a reactive, unstable acyl glucuronide which accumulates in plasma. Because of the similarity of zomepirac glucuronide to bilirubin glucuronide in structure and stability and the documented irreversible binding of bilirubin to albumin through its acyl glucuronide, we studied the reaction of zomepirac acyl glucuronide with albumin in vitro from pH 5 to 9 and in vivo in six healthy human volunteers who had received a single 100-mg oral dose of zomepirac. Irreversible binding of zomepirac to protein was determined by exhaustive washing of protein, followed by hydrolysis of bound zomepirac-protein adduct with base, extraction of the liberated drug, and chromatographic measurement. Irreversible binding was observed both in vitro and in vivo. The extent of binding in vitro was time- and pH-dependent. In vitro drug binding was also observed for the isomers of zomepirac glucuronide which were formed by intramolecular acyl migration. Irreversible binding in vivo correlated with overall exposure to zomepirac glucuronide when exposure was expressed as the area under the plasma concentration vs. time curve. When probenecid (500 mg, twice daily), which decreases the plasma clearance of zomepirac glucuronide, was administered concurrently with zomepirac, irreversible binding of zomepirac was increased. The nature of the zomepirac protein binding is probably covalent. Formation of irreversibly protein-bound zomepirac occurs via the acyl glucuronide as previously shown for bilirubin glucuronide, and the reaction may be general for other drugs that are metabolized to acyl glucuronides.
佐美酸是一种非甾体抗炎药，最近因其免疫反应发生率高且原因不明而被停用。它在人体内代谢为一种具有反应活性、不稳定的酰基葡萄糖醛酸，这种物质会在血浆中蓄积。由于佐美酸葡萄糖醛酸在结构和稳定性上与胆红素葡萄糖醛酸相似，且有文献记载胆红素通过其酰基葡萄糖醛酸与白蛋白发生不可逆结合，我们研究了佐美酸酰基葡萄糖醛酸在体外pH值为5至9时与白蛋白的反应，以及在6名健康人类志愿者体内的反应，这些志愿者单次口服了100毫克佐美酸。通过彻底洗涤蛋白质，然后用碱水解结合的佐美酸 - 蛋白质加合物，提取释放出的药物，并进行色谱测量，来确定佐美酸与蛋白质的不可逆结合。在体外和体内均观察到了不可逆结合。体外结合程度与时间和pH值有关。佐美酸葡萄糖醛酸通过分子内酰基迁移形成的异构体在体外也观察到了药物结合。当以血浆浓度 - 时间曲线下面积表示暴露量时，体内不可逆结合与佐美酸葡萄糖醛酸的总体暴露量相关。当与佐美酸同时给予丙磺舒（500毫克，每日两次）时，丙磺舒会降低佐美酸葡萄糖醛酸的血浆清除率，此时佐美酸的不可逆结合增加。佐美酸与蛋白质结合的性质可能是共价的。如先前对胆红素葡萄糖醛酸所示，不可逆结合的佐美酸是通过酰基葡萄糖醛酸形成的，并且该反应可能对其他代谢为酰基葡萄糖醛酸的药物也普遍适用。
