Ge Shufan, Tu Yifan, Hu Ming
Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, The University of Houston, 1441 Moursund Street, Houston, TX, 77030, USA.
Curr Pharmacol Rep. 2016 Dec;2(6):326-338. doi: 10.1007/s40495-016-0076-8. Epub 2016 Nov 8.
Glucuronidation is the most important phase II metabolic pathway which is responsible for the clearance of many endogenous and exogenous compounds. To better understand the elimination process for compounds undergoing glucuronidation and identify compounds with desirable in vivo pharmacokinetic properties, many efforts have been made to predict glucuronidation using data. In this article, we reviewed typical approaches used in previous predictions. The problems and challenges in prediction of glucuronidation were discussed. Besides that different incubation conditions can affect the prediction accuracy, other factors including efflux / uptake transporters, enterohepatic recycling, and deglucuronidation reactions also contribute to the disposition of glucuronides and make the prediction more difficult. PBPK modeling, which can describe more complicated process , is a promising prediction strategy which may greatly improve the prediction of glucuronidation and potential DDIs involving glucuronidation. Based on previous studies, we proposed a transport-glucuronidation classification system, which was built based on the kinetics of both glucuronidation and transport of the glucuronide. This system could be a very useful tool to achieve better predictions.
葡萄糖醛酸化是最重要的Ⅱ相代谢途径，负责清除许多内源性和外源性化合物。为了更好地理解经历葡萄糖醛酸化的化合物的消除过程，并识别具有理想体内药代动力学性质的化合物，人们已做出诸多努力利用数据预测葡萄糖醛酸化。在本文中，我们回顾了先前预测中使用的典型方法。讨论了葡萄糖醛酸化预测中的问题和挑战。除了不同的孵育条件会影响预测准确性外，其他因素包括外排/摄取转运体、肠肝循环和去葡萄糖醛酸化反应也会影响葡萄糖醛酸苷的处置，使预测更加困难。生理药代动力学（PBPK）建模能够描述更复杂的过程，是一种很有前景的预测策略，可能会极大地改善葡萄糖醛酸化及涉及葡萄糖醛酸化的潜在药物相互作用的预测。基于先前的研究，我们提出了一种转运-葡萄糖醛酸化分类系统，该系统基于葡萄糖醛酸化和葡萄糖醛酸苷转运的动力学构建。该系统可能是实现更好预测的非常有用的工具。
