Sallustio B C, Fairchild B A, Pannall P R
Department of Clinical Pharmacology, Queen Elizabeth Hospital, Woodville, South Australia.
Drug Metab Dispos. 1997 Jan;25(1):55-60.
Acyl glucuronides are electrophilic metabolites that are readily hydrolyzed, undergo intramolecular rearrangement, and bind covalently to endogenous proteins. Gemfibrozil is a fibrate lipid-lowering agent that is extensively metabolized to an acyl glucuronide conjugate in humans. The aims of this study were to examine the interactions of 1-O-gemfibrozil-beta-D-glucuronide with human serum albumin. The degradation of 1-O-gemfibrozil-beta-D-glucuronide (approximately 200 microM) was examined in vitro during incubations at 37 degrees C with phosphate buffer (pH 7.4 or 9.0), solutions of human serum albumin (pH 7.4), or fresh human plasma (pH 7.4). The effects of diazepam, oxyphenbutazone, and gemfibrozil on the degradation of 1-O-gemfibrozil-beta-D-glucuronide, and its reversible binding to albumin were also studied. A pilot in vivo study was performed on two patient volunteers administered 1 g/day p.o. gemfibrozil. 1-O-Gemfibrozil-beta-D-glucuronide was unstable, with degradation half-lives in buffer of 4.1 hr and 44 hr at pH 9.0 and 7.4, respectively; and 8.5 hr and 5.5 hr in pH 7.4 solutions of human serum albumin or fresh plasma, respectively. Degradation was dependent on pH and the presence of albumin, which seemed to accelerate the intramolecular rearrangement and hydrolysis of the conjugate. 1-O-Gemfibrozil-beta-D-glucuronide was highly reversibly bound to albumin, with a mean unbound fraction of 0.028, and its degradation seemed to be related to the degree of reversible binding. Hydrolysis and covalent binding were associated with the site II binding domain on albumin, because only diazepam inhibited these reactions. However, intramolecular rearrangement was increased when binding to the site I domain was inhibited. Covalent binding was also detected in vivo to human plasma proteins. The half-life of the gemfibrozil-protein adducts was 2.5-3 days. Albumin plays an important role in the disposition of acyl glucuronides by acting as: i) a transporter protein; ii) a potential catalyst for their degradation and, therefore, clearance; and iii) a target for covalent adduct formation.
酰基葡萄糖醛酸是亲电代谢产物，易水解，发生分子内重排，并与内源性蛋白质共价结合。吉非贝齐是一种贝特类降脂药物，在人体内广泛代谢为酰基葡萄糖醛酸共轭物。本研究的目的是研究1-O-吉非贝齐-β-D-葡萄糖醛酸与人类血清白蛋白的相互作用。在37℃下，将1-O-吉非贝齐-β-D-葡萄糖醛酸（约200 microM）与磷酸盐缓冲液（pH 7.4或9.0）、人类血清白蛋白溶液（pH 7.4）或新鲜人类血浆（pH 7.4）一起孵育，检测其体外降解情况。还研究了地西泮、羟苯丁宗和吉非贝齐对1-O-吉非贝齐-β-D-葡萄糖醛酸降解及其与白蛋白可逆结合的影响。对两名口服吉非贝齐1 g/天的患者志愿者进行了一项初步体内研究。1-O-吉非贝齐-β-D-葡萄糖醛酸不稳定，在pH 9.0和7.4的缓冲液中降解半衰期分别为4.1小时和44小时；在pH 7.4的人类血清白蛋白溶液或新鲜血浆中分别为8.5小时和5.5小时。降解取决于pH值和白蛋白的存在，白蛋白似乎加速了共轭物的分子内重排和水解。1-O-吉非贝齐-β-D-葡萄糖醛酸与白蛋白高度可逆结合，平均未结合分数为0.028，其降解似乎与可逆结合程度有关。水解和共价结合与白蛋白上的位点II结合域有关，因为只有地西泮能抑制这些反应。然而，当与位点I域的结合被抑制时，分子内重排增加。体内也检测到与人类血浆蛋白的共价结合。吉非贝齐-蛋白质加合物的半衰期为2.5-3天。白蛋白在酰基葡萄糖醛酸的处置中起重要作用，其作用如下：i）转运蛋白；ii）其降解及因此清除的潜在催化剂；iii）共价加合物形成的靶点。
