Soars M G, Burchell B, Riley R J
Department of Molecular and Cellular Pathology, Ninewells Hospital and Medical School, Dundee, Scotland.
J Pharmacol Exp Ther. 2002 Apr;301(1):382-90. doi: 10.1124/jpet.301.1.382.
The glucuronidation of a number of commonly used hepatic uridine diphosphate glucuronosyltransferase drug substrates has been studied in human tissue microsomes. Prediction of in vivo hepatic drug glucuronidation from liver microsomal data yielded a consistent 10-fold under-prediction. Consideration of protein binding was observed to be pivotal when predicting in vivo glucuronidation for acid substrates. Studies using human intestinal microsomes demonstrated the majority of drugs to be extensively glucuronidated such that the intrinsic clearance (CL(int)) of ethinylestradiol (CL(int) = 1.3 microl/min/mg) was twice that obtained using human liver microsomes (CL(int) = 0.7 microl/min/mg). The potential extrahepatic in vivo glucuronidation was calculated for a range of drug substrates from human microsomal data. These results indicate the contribution of intestinal drug glucuronidation to systemic drug clearance to be much less than either hepatic or renal glucuronidation. Therefore, data obtained with intestinal microsomes may be misleading in the assessment of the contribution of this organ to systemic glucuronidation. The use of hepatocytes to assess metabolic stability for drugs predominantly metabolized by glucuronidation was also investigated. Metabolic clearances for a range of drugs obtained using fresh preparations of human hepatocytes predicted accurately hepatic clearance reported in vivo. The use of cryopreserved hepatocytes as an in vitro tool to predict in vivo metabolism was also assessed with an excellent correlation obtained for a number of extensively glucuronidated drugs (R(2) = 0.80, p < 0.001).
在人组织微粒体中研究了多种常用的肝脏尿苷二磷酸葡萄糖醛酸基转移酶药物底物的葡萄糖醛酸化作用。根据肝脏微粒体数据预测体内肝脏药物葡萄糖醛酸化作用时，结果始终低预测了10倍。在预测酸性底物的体内葡萄糖醛酸化作用时，观察到考虑蛋白质结合是关键。使用人肠道微粒体的研究表明，大多数药物会被广泛葡萄糖醛酸化，以至于炔雌醇的内在清除率（CL(int)=1.3微升/分钟/毫克）是使用人肝脏微粒体时获得的清除率（CL(int)=0.7微升/分钟/毫克）的两倍。根据人微粒体数据计算了一系列药物底物的潜在肝外体内葡萄糖醛酸化作用。这些结果表明，肠道药物葡萄糖醛酸化作用对全身药物清除率的贡献远小于肝脏或肾脏的葡萄糖醛酸化作用。因此，在评估该器官对全身葡萄糖醛酸化作用的贡献时，肠道微粒体获得的数据可能会产生误导。还研究了使用肝细胞评估主要通过葡萄糖醛酸化作用代谢的药物的代谢稳定性。使用新鲜的人肝细胞制剂获得的一系列药物的代谢清除率准确预测了体内报告的肝脏清除率。还评估了使用冷冻保存的肝细胞作为预测体内代谢的体外工具，对于许多广泛葡萄糖醛酸化的药物获得了极好的相关性（R(2)=0.80，p<0.001）。
