Contribution of cytochrome P450 isoforms to gliquidone metabolism in rats and human
Contribution of cytochrome P450 isoforms to gliquidone metabolism in rats and human
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DOI：
10.3109/00498254.2013.831957
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发表时间：
2014-02
期刊：
影响因子：
1.8
通讯作者：
Fang He;Yun Li;Caiwen Zeng;Chunhua Xia;Y. Xiong;Hong Zhang;Shibo Huang;Mingyi Liu
中科院分区：
文献类型：
--
作者：
Fang He;Yun Li;Caiwen Zeng;Chunhua Xia;Y. Xiong;Hong Zhang;Shibo Huang;Mingyi Liu
抽象的1。格列酮是一种广泛使用的口服降糖药，是第二代磺脲类药物。由于其代谢速率的差异，格列酮在药代动力学和药效学方面表现出不同受试者之间的差异。2. 细胞色素P450 （CYP450）异构体参与临床使用的大多数药物的代谢，并在减少可能的药物相互作用方面发挥重要作用。本研究旨在系统研究人类多种CYP450亚型对大鼠和人体外格列酮代谢的贡献。3. 在大鼠肝微粒体中，格列酮主要由最丰富的CYP2C代谢。参与代谢的其他亚型包括CYP3A、CYP2D、CYP1A和CYP2E。4. 对大鼠重组酶的进一步研究表明，CYP3A1和CYP2C11在体外代谢中起主要作用，同时CYP2D1、CYP1A2和CYP2E1也参与了体外代谢。5. 而格列酮在人肝微粒体中的代谢主要由CYP3A4介导。参与这一过程的其他同工异构体有CYP2C9、CYP2C19和CYP2D6。6. 对人重组酶的进一步研究表明，CYP3A4是格列酮代谢的主要同工异构体酶。CYP3A4的内在清除率（Vmax/Km）是其他CYP450亚型CYP2C9、CYP2D6和CYP2C19的3-12倍。7. 这些发现可能有助于有价值地预测格列酮与其他CYP3A4抑制剂或诱导剂药物的潜在相互作用，并有助于设计更有效和更安全的药物治疗糖尿病患者。
Abstract 1. Gliquidone, a second generation sulfonylurea, is a widely used oral antidiabetic drug. Due to the differences in its rate of metabolism, gliquidone shows inter-subject variability in pharmacokinetic and pharmacodynamic profiles. 2. Cytochrome P450 (CYP450) isoforms are involved in the metabolism of a majority of drugs in clinical use and plays a significant role in reducing possible drug interactions. This research aimed to systematically study the contribution of various human CYP450 isoforms to gliquidone metabolism in vitro in rats and human. 3. In rat liver microsomes, gliquidone was metabolized mainly by the most abundant CYP2C. The other isoforms involved in the metabolism included CYP3A, CYP2D, CYP1A and CYP2E. 4. Further investigation of rat recombinant enzymes showed that CYP3A1 and CYP2C11 played a major role in gliquidone metabolism in vitro, while CYP2D1, CYP1A2 and CYP2E1 were also involved. 5. But the metabolism of gliquidone in the human liver microsomes was mainly mediated by CYP3A4. The other isoforms involved in this process were CYP2C9, CYP2C19 and CYP2D6. 6. The further study of human recombinant enzymes demonstrated that CYP3A4 was the principal isoform enzyme for the metabolism of gliquidone. The intrinsic clearance (Vmax/Km) of CYP3A4 during gliquidone metabolism was 3–12 times greater than that of other CYP450 isoforms including CYP2C9, CYP2D6 and CYP2C19. 7. These findings may assist in valuable prediction of potential interactions of gliquidone with other drugs that are CYP3A4 inhibitors or inducers and help to design more efficacious and safer pharmacotherapy for patients of diabetes mellitus.