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体外“鸡尾酒法”研究5-羟基雷公藤内酯醇对人肝微粒体CYP450酶亚型的抑制 被引量：4

Inhibition study of cytochrome P450 isozymes by (5R)-5-hydroxytriptolide using in vitro “cocktail” method
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摘要 目的:评价(5R)-5-羟基雷公藤内酯醇(T8)在体外对人肝微粒体CYP450酶7种主要亚型CYP3A/5、CYP2D6、CYP1A2、CYP2C9、CYP2C19、CYP2B6和CYP2C8的直接抑制作用和时间依赖性抑制作用,为临床药物-药物相互作用研究提供指导。方法:本实验分别利用IC50和IC50偏移进行评价。结果:T8对上述7种亚型的直接抑制IC50都高于100μmol/L,时间依赖性抑制研究中没有出现IC50偏移。结论:T8对7种主要的CYP450酶亚型没有直接抑制和时间依赖性抑制作用。临床上发生由于T8抑制上述7种亚型的CYP450酶导致的药物-药物相互作用的可能性较小。 AIM： To evaluate whether 5- hydroxytriptolide （T8） is a direct inhibitior or time-dependent inhibitor of CYP3A/5, CYP2D6, CYP2C9, CYPIA2, CYP2C19, CYP2B6 and CYP2C8, and to evaluate the potential of drug-drug interaction with the sub strates of above seven CYPs in clinical study, which provide a reference for clinical drug-drug interaction study. METHODS： IC50 and IC50 shift method were used in this study. RESULTS： The IC50 of T8 on above seven CYPs was more than100 μmol/L in direct inhibition experiment, and no IC50 shift occurred in time-dependent inhibition experiment. CONCLUSION： T8 is neither a direct inhibitor nor time-dependent inhibitor of above seven CYPs, and the potential of drugdrug interaction caused by T8 inhibition on CYP450 isozymes is slim.
作者 刘海燕 张乐多 向志雄 苗红
机构地区 上海医药集团股份有限公司中央研究院
出处 《中国临床药理学与治疗学》 CAS CSCD 2013年第11期1211-1218,共8页 Chinese Journal of Clinical Pharmacology and Therapeutics
基金 新药创制重大专项(2009ZX09102):一类新药雷腾舒的临床前研究
关键词 5-羟基雷公藤内酯醇 CYP450 直接抑制 时间依赖性抑制 5-hydroxytriptolide CYP450Direct inhibition Time-dependent inhibition
分类号 R965.2 [医药卫生—药理学]
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参考文献15

  • 1Zhou R, Tang W, Ren YX, et al. (5R)-5- hydroxytriptolide attenuated collagen-induced arthritis in DBA/1 mice via suppressing interferon- gamma production and its related signaling[J]. J Pharmaeol Exp Ther, 2006,318(1) :35-44.
  • 2Zhou R, Wang JX, Tang W, et al. (5R)-5 hydroxytriptolide inhibits IFN-gamma-retated sig naling[J]. Acta Pharmacol Sin, 2006, 27 (12) 1616-1621.
  • 3Fu YF, Zhu YN, Ni J, et al. (SR)-5-hydroxytrip- tolide (LLDT-8), a novel triptolide derivative, prevents experimental autoimmune encephalomye- litis via inhibiting T cell activation[J]. J Neuroimmunol, 2006, 175(1/2):142-151.
  • 4Zhou R, Zhang F, He PL, et al. (SR)-5- hydroxytriptolide (LLDT-8), a novel triptolide analog mediates immunosuppressive effects in vitro and in vivo [J]. Int Immunopharmacol, 2005, 5(13/14) :1895-1903.
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  • 6Otten JN, Hingorani GP, Hartley DP, et al. An In vitro, High Throughput, Seven CYP Cocktail In- hibition Assay for the Evaluation of New Chemical Entities Using LC-MS/MS [J]. Drug Metab Lett, 2011,5(1):17-24.
  • 7Testino SA Jr, Patonay G. High-throughput inhibi- tion screening of major human cytochrome P450 enzymes using an in vitro cocktail and liquid chro- matography-tandem mass spectrometry [ J ]. J Pharm Biomed Anal, 2003, 30(5) :1459-1467.
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同被引文献30

  • 1LEVITZKI A. Tyrosine kinase inhibitors:views of selectivity, sen- sitivity, and clinical performance [ J ]. Annu Rev Pharmacol Toxi- col,2013,53:161 - 185.
  • 2RUSCONI F, PIAZZA R, VAGGE E, et al. Bosutinib : a review of preclinieal and clinical studies in chronic myelogenous leukemia [ J]. Expert Opin Pharmacother,2014, 15 (5) :701 - 710.
  • 3MESSERSMITH WA, RAJESHKUMAR NV,TAN AC, et al. Effi- cacy and pharmacodynamic effects of bosutinib ( SKI-606 ) , a Src/Abl inhibitor, in freshly generated human pancreas cancer xenografts[ J]. Mol Cancer Ther,2009,8 ( 6 ) : 1484 - 1493.
  • 4FDA guidance. Drug FDA guidance. Drug interaction studies-study design data analysis,implications for dosing, and labeling recom- mendations [ S ]. 2012.
  • 5OTTEN JN, HINGORANI GP, HARTLEY DP,et al. An in vitro, high throughput,seven CYP cocktail inhibition assay for the eval- uation of new chemical entities using LC-MS/MS[ Jl. Drug Metab Lett,2011,5(1 ) :17 -24.
  • 6TESTINO SA JR,PATONAY G. High-throughput inhibition screening of major human eytochrome P450 enzymes using an in vitro cock- tail and liquid chromatography-tandem mass spectrometry [ J]. J Pharm Biomed Anal,2003,30 ( 5 ) : 1459 - 1467.
  • 7O'DONNELL C J, GRIME K, COURTNEY P, et al. The develop- ment of a cocktail CYP2B6 ,CYP2C8 ,and CYP3A5 inhibition as- say and a preliminary assessment of utility in a drug discovery set- ting[ J]. Drug Metab Dispos,2007,35 ( 3 ) :381 - 385.
  • 8TURPEINEN M,NIEMINEN R, JUNTUNEN T, et al. Selective inhibition of CYP2B6-catalyzed bupropion hydroxylation in hu- man liver microsomes in vitro [ J ]. Drug Metab Dispos , 2004,32 (6) :626 -631.
  • 9ATKINSON A, KENNY JR, GRIME K. Automated assessment of time-dependent inhibition of human cytochrome P450 enzymes u- sing liquid chromatography-tandem mass spectrometry analysis [ J ]. Drug Metab Dispos, 2005,33 ( 11 ) : 1637 - 1647.
  • 10STRESSER DM, MASON AK, PERLOFF ES, et al. Differential time-and NADPH-dependent inhibition of CYP2C19 by enanti- omers of fluoxetine [ J ]. Drug Metab Dispos, 2009,37 ( 4 ) : 695 - 698.

引证文献4

二级引证文献21

中国临床药理学与治疗学
2013年 第11期

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