Glucuronidation: driving factors and their impact on glucuronide disposition.
Glucuronidation: driving factors and their impact on glucuronide disposition.
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DOI：
10.1080/03602532.2017.1293682
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发表时间：
2017-05
影响因子：
5.9
通讯作者：
Hu M
中科院分区：
文献类型：
--
作者：
Yang G;Ge S;Singh R;Basu S;Shatzer K;Zen M;Liu J;Tu Y;Zhang C;Wei J;Shi J;Zhu L;Liu Z;Wang Y;Gao S;Hu M
葡萄糖醛酸化是公认的多种化学物质（包括药物和内源性物质）的II期代谢途径。虽然它通常是在I相羟基化之前的化合物的次级代谢途径，但葡萄糖醛酸化本身可以作为主要的代谢途径化合物，包括一些具有高水溶性的化合物。葡萄糖醛酸化涉及母体化合物通过udp -葡萄糖醛酸基转移酶（UGTs）代谢成亲水性和带负电荷的葡萄糖醛酸盐，如果没有外排转运体的帮助，这些葡萄糖醛酸盐不能离开细胞。因此，在代谢活跃的细胞中，通过葡萄糖醛酸化消除母体化合物是由两个驱动力控制的；由UGT酶形成的葡萄糖醛酸盐，以及这些葡萄糖醛酸盐通过位于各种药物处置器官细胞表面的外排转运体（极化）排泄。与通常的假设相反，到达体循环的葡萄糖醛酸盐最终被尿液排泄，最近的证据表明，肝细胞能够高效地清除肠道产生的葡萄糖醛酸盐。此外，胆道和肠道消除的葡萄糖醛酸苷参与了涉及肠道微生物的再循环计划，这通常会延长其局部和全身暴露时间，尽管全身浓度较低。综上所述，这些最近的研究进展表明，虽然UGT决定了葡萄糖醛酸生成的速度和程度，但外排和摄取转运体决定了这些葡萄糖醛酸进入血液然后进入各器官消除的分布。除了延长母体化合物在肠道和结肠的暴露时间外，回收方案还会影响母体化合物及其到达肠腔的葡萄糖醛酸盐的血浆表观半衰期。
Glucuronidation is a well-recognized phase II metabolic pathway for a variety of chemicals including drugs and endogenous substances. Although it is usually the secondary metabolic pathway for a compound preceded by phase I hydroxylation, glucuronidation alone could serve as the dominant metabolic pathway compounds, including some with high aqueous solubility. Glucuronidation involves the metabolism of parent compound by UDP-glucuronosyltransferases (UGTs) into hydrophilic and negatively charged glucuronides that cannot exit the cell without the aid of efflux transporters. Therefore, elimination of parent compound via glucuronidation in a metabolic active cell is controlled by two driving forces; the formation of glucuronides by UGT enzymes and the (polarized) excretion of these glucuronides by efflux transporters located on the cell surfaces in various drug disposition organs. Contrary to the common assumption that the glucuronides reaching the systemic circulation were destined for urinary excretion, recent evidences suggest that hepatocytes are capable of highly efficient biliary clearance of the gut-generated glucuronides. Furthermore, the biliary- and enteric-eliminated glucuronides participate into recycling schemes involving intestinal microbes, which often prolong their local and systemic exposure, albeit at low systemic concentrations. Taken together, these recent research advances indicate that though UGT determines the rate and extent of glucuronide generation, the efflux and uptake transporters determine the distribution of these glucuronides into blood and then to various organs for elimination. Recycling schemes impact the apparent plasma half-life of parent compounds and their glucuronides that reach intestinal lumen, in addition to prolonging their gut and colon exposure.
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影响因子：
3.3
作者：
Bortfeld, M;Rius, M;Keppler, D
通讯作者：
Keppler, D
影响因子：
2.1
作者：
An, Guohua;Morris, Marilyn E.
通讯作者：
Morris, Marilyn E.
影响因子：
3.6
作者：
Chen, ZS;Hopper-Borge, E;Kruh, GD
通讯作者：
Kruh, GD
DOI：
10.1073/pnas.102187299
发表时间：
2002-05-14
影响因子：
11.1
作者：
Bera, TK;Iavarone, C;Pastan, I
通讯作者：
Pastan, I
DOI：
10.1111/j.1742-4658.2011.08235.x
发表时间：
2011-09
期刊：
The FEBS journal
影响因子：
--
作者：
Chen ZS;Tiwari AK
通讯作者：
Tiwari AK