Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Punjab, India.
Drug Metab Rev. 2013 May;45(2):231-52. doi: 10.3109/03602532.2013.767345. Epub 2013 Mar 6.
The current drug development process aims to produce safe, effective drugs within a reasonable time and at a reasonable cost. Phase II metabolism (glucuronidation) can affect drug action and pharmacokinetics to a considerable extent and so its studies and prediction at initial stages of drug development are very imperative. Extensive glucuronidation is an obstacle to oral bioavailability because the first-pass glucuronidation [or premature clearance by UDP-glucuronosyltransferases (UGTs)] of orally administered agents frequently results in poor oral bioavailability and lack of efficacy. Modeling of new chemical entities/drugs for UGTs and their kinetic data can be useful in understanding the binding patterns to be used in the design of better molecules. This review concentrates on first-pass glucuronidation by intestinal UGTs, including their topology, expression profile, and pharmacogenomics. In addition, recent advances are discussed with respect to substrate selectivity at the binding pocket, structural requirements, and mechanism of enzyme actions.
当前的药物开发过程旨在在合理的时间和合理的成本内生产安全、有效的药物。Ⅱ期代谢（葡萄糖醛酸化）可以在相当大的程度上影响药物作用和药代动力学，因此在药物开发的早期阶段对其进行研究和预测非常必要。广泛的葡萄糖醛酸化是口服生物利用度的障碍，因为口服给予的药物的首过葡萄糖醛酸化[或通过 UDP-葡糖醛酸基转移酶（UGTs）的过早清除]常常导致口服生物利用度差和疗效不足。对 UGTs 的新化学实体/药物进行建模及其动力学数据有助于了解用于设计更好分子的结合模式。这篇综述集中讨论了肠道 UGTs 的首过葡萄糖醛酸化，包括它们的拓扑结构、表达谱和药物基因组学。此外，还讨论了结合口袋的底物选择性、结构要求和酶作用机制方面的最新进展。
