短刺小克银汉霉AS3.910的CYP2C9同工酶抑制作用  

The inhibition of CYP2C9 isoenzyme in Cunninghamella blakesleeana AS 3.910

作　　者：林立红[1] 黄海华 张鹏[1] 钟大放[3] 

机构地区：[1]沈阳药科大学,辽宁沈阳110016 [2]上海药代生物科技有限公司,上海201204 [3]中国科学院上海药物研究所,上海201203

出　　处：《药学学报》2006年第10期967-972,共6页Acta Pharmaceutica Sinica

基　　金：国家高技术研究发展计划(863计划)资助项目(2005AA2Z3C70).

摘　　要：目的探索具有药物代谢酶CYP2C9活性的微生物模型对CYP2C9抑制剂的响应。方法选用短刺小克银汉霉AS 3.910为模型菌株,检测CYP2C9抑制剂对CYP2C9底物特定转化产物产率的影响,并通过底物间相互影响的程度探索该转化体系中的药物代谢相互作用。采用液相色谱-多级质谱联用技术检测转化产物。结果CYP2C9抑制剂苯溴马隆抑制4′-羟基甲苯磺丁脲的生成,使其产率由100%下降到14.5%;磺胺苯吡唑抑制O-去甲基吲哚美辛的生成,使其产率由75.2%降低到9.9%;丙戊酸抑制4′-羟基双氯芬酸的生成,使其产率由98.6%降低到2.7%。底物药物甲苯磺丁脲、双氯芬酸和吲哚美辛之间存在代谢相互作用,导致生成相应代谢物的产率降低。结论3种CYP2C9抑制剂不同程度地抑制了短刺小克银汉霉的CYP2C9同工酶,而且CYP2C9底物间存在药物代谢相互作用。Aim To investigate the variation of CYP2C9 isoenzyme activity in the microbial model in response to inhibitors of CYP2C9. Methods Using C. blakesleeana AS 3. 910 as a model strain, the impact of CYP2C9 inhibitors on the metabolites yields of CYP2C9 substrates was determined and the drugdrug interactions among CYP2C9 substrates were evaluated. Liquid chromatography-mass spectrometry was used to analyze biotransformation products. Results Benzbromarone decreased the yield of 4＇- hydroxytolbutamide from 100% to 14.5% ; sulfaphenazole decreased the yield of O-demethylindomethacin from 75.2% to 9.9% ; valproic acid decreased the yield of 4＇-hydroxydiclofenac from 98.6% to 2.7% , separately. Tolbutamide, indomethacin and diclofenac interacted with each other, resulting in the decreased formation of metabolites catalyzed by CYP2C9. Conclusion Three CYP2C9 inhibitors inhibit the activity of CYP2C9 isoenzyme in C. blakesleeana AS 3. 910 differently, and there are drug-drug interactions among CYP2C9 substrates.

关 键 词：细胞色素P450 CYP2C9 短刺小克银汉霉 药物代谢 同工酶 酶抑制剂 

分 类 号：R968.1[医药卫生—药理学]