Sallustio B C, Fairchild B A, Shanahan K, Evans A M, Nation R L
Department of Clinical Pharmacology, Queen Elizabeth Hospital, Woodville, South Australia.
Drug Metab Dispos. 1996 Sep;24(9):984-9.
Acyl glucuronides are reactive electrophilic metabolites and in vivo are readily hydrolyzed, undergo intramolecular rearrangement, and bind covalently to proteins. The isolated perfused liver preparation, using male Sprague-Dawley rats, was used to examine the hepatic disposition of the fibrate hypolipidemic agent gemfibrozil and its acyl glucuronide metabolite, 1-O-gemfibrozil-beta-D-glucuronide. Using a recirculating design, erythrocyte-free perfusion medium containing 1% (w/v) albumin was delivered to the liver via the portal vein at a flow rate of 30 ml/min, and for each experiment was spiked with either gemfibrozil (N = 4) or 1-O-gemfibrozil-beta-D-glucuronide (N = 4) at initial concentrations of 120 microM and 21 microM, respectively. In the gemfibrozil perfusions, the mean (SD) total perfusate clearance, half-life, hepatic extraction ratio of gemfibrozil, and the fraction of eliminated gemfibrozil excreted in bile as the glucuronide conjugate were 2.73 (0.30) ml/min, 76.9 (5.6) min, 0.091 (0.012), and 0.347 (0.154), respectively. In the 1-O-gemfibrozil-beta-D-glucuronide perfusions, the mean (SD) total perfusate clearance, half-life, hepatic extraction ratio, and fraction excreted in bile as the glucuronide conjugate were 19.5 (2.1) ml/min, 8.7 (0.9) min, 0.649 (0.068), and 0.534 (0.077), respectively. The higher hepatic extraction ratio for 1-O-gemfibrozil-beta-D-glucuronide could mostly be attributed to its higher unbound fraction in perfusate (0.182), compared with that of the parent drug (0.004), because the conjugate had a lower intrinsic clearance (305 ml/min) compared with the aglycone (751 ml/min). Control perfusions, conducted in the absence of a liver, showed negligible degradation of 1-O-gemfibrozil-beta-D-glucuronide over 90 min. However, in the presence of a liver, approximately 25% of 1-O-gemfibrozil-beta-D-glucuronide added to perfusate was hydrolyzed to gemfibrozil over 90 min. The study demonstrates the importance of the liver in the formation, uptake, hydrolysis, and excretion of 1-O-gemfibrozil-beta-D-glucuronide.
酰基葡萄糖醛酸是具有反应活性的亲电代谢产物，在体内易于水解，发生分子内重排，并与蛋白质共价结合。使用雄性斯普拉格 - 道利大鼠的离体灌注肝脏制备物，用于研究贝特类降血脂药物吉非贝齐及其酰基葡萄糖醛酸代谢物1 - O - 吉非贝齐 - β - D - 葡萄糖醛酸的肝脏处置情况。采用循环设计，含1%（w/v）白蛋白的无红细胞灌注介质以30 ml/min的流速通过门静脉输送至肝脏，每次实验分别加入初始浓度为120 μM的吉非贝齐（N = 4）或21 μM的1 - O - 吉非贝齐 - β - D - 葡萄糖醛酸（N = 4）。在吉非贝齐灌注实验中，吉非贝齐的平均（标准差）总灌注液清除率、半衰期、肝脏提取率以及以葡萄糖醛酸缀合物形式经胆汁排泄的消除吉非贝齐分数分别为2.73（0.30）ml/min、76.9（5.6）min、0.091（0.012）和0.347（0.154）。在1 - O - 吉非贝齐 - β - D - 葡萄糖醛酸灌注实验中，平均（标准差）总灌注液清除率、半衰期、肝脏提取率以及以葡萄糖醛酸缀合物形式经胆汁排泄的分数分别为19.5（2.1）ml/min、8.7（0.9）min、0.649（0.068）和0.534（0.077）。1 - O - 吉非贝齐 - β - D - 葡萄糖醛酸较高的肝脏提取率主要归因于其在灌注液中的较高游离分数（0.182），相比之下母体药物的游离分数为0.004，因为该缀合物的内在清除率（305 ml/min）低于苷元（751 ml/min）。在无肝脏存在的情况下进行的对照灌注实验显示，90分钟内1 - O - 吉非贝齐 - β - D - 葡萄糖醛酸的降解可忽略不计。然而，在有肝脏存在的情况下，添加到灌注液中的1 - O - 吉非贝齐 - β - D - 葡萄糖醛酸在90分钟内约有25%水解为吉非贝齐。该研究证明了肝脏在1 - O - 吉非贝齐 - β - D - 葡萄糖醛酸的形成、摄取、水解和排泄中的重要性。
