银杏黄酮的体外葡醛酸反应及其药物相互作用  

Glucuronidation and in vitro interaction of Ginkgo flavonoids with other drugs

作　　者：诸敏[1] 姚彤炜[1] 曾苏[1] 

机构地区：[1]浙江大学药学院药物分析与药物代谢研究室

出　　处：《浙江大学学报（医学版）》2004年第1期15-20,共6页Journal of Zhejiang University(Medical Sciences)

基　　金：浙江省自然科学基金 (30 2 6 82 ) ;浙江省经贸委中药现代化专项基金 ;杭州市卫生局课题 (0 2 A0 18)

摘　　要：目的 :获得银杏黄酮体外代谢情况 ,预测银杏叶制剂与常用心血管类药物之间的代谢性相互作用的可能性。方法 :银杏黄酮与普罗帕酮、硝苯地平、地非三唑和依普黄酮在经 β-萘黄酮诱导的鼠肝微粒体中共孵育 ,以HPLC法测定孵育液中剩余银杏黄酮的浓度 ,观察共孵育药物对银杏黄酮葡醛酸结合反应的影响 ,并计算银杏黄酮 3个苷元的酶动力学参数。结果 :测得银杏黄酮槲皮素、异鼠李素和山奈酚的 Vmax值分别为 (6 0± 0 .2 1)、(48±0 .0 2 )、(34± 0 .0 2 )μmol· g-1· min-1,Km 值分别为 (2 4± 0 .0 5 )、(14 8± 0 .0 9)、(110± 0 .0 3)μmol/ L ;当银杏黄酮浓度一定时 ,共孵育药物硝苯地平、普罗帕酮、依普黄酮和地非三唑对银杏黄酮的 IC50 分别为 5 4～ 70、6 9～ 12 2、85～98和 2 10～ 36 2 μmol。测得地非三唑对银杏黄酮 3种苷元的抑制常数 Ki值分别为 5 7.6、5 0 .5和 33.1mg/ L;普罗帕酮的 Ki值分别为 33.6、5 9.5和 4 5 .2 mg/ L;依普黄酮的 Ki值分别为 13.7、2 4 .0和 15 .7mg/ L。普罗帕酮的 [I]/[Ki]比值为 0 .0 0 2～ 0 .0 0 3。结论 :在银杏黄酮的 3种苷元中槲皮素的代谢能力最强 ;硝苯地平、依普黄酮和普罗帕酮等对槲皮素、异鼠李素和山奈酚的葡醛酸反应均有不同程度的抑制作用 ;Objective: To obtain the information on the glucuronidation of Ginkgo flavonoid and the interaction profile of Ginkgo flavones with other drugs in vitro. Methods: Ginkgo flavonoids (quercetin,isorhamnetin and keampferol) and other drugs were co-incubated with rat hepatic microsome at 25℃; the residual concentrations of flavonoids were determined by HPLC. The enzymatic parameters of quercetin,isorhamnetin and keampferol metabolism were assessed. The interactions between flavonoids and these drugs on glucuronidation were observed. Results: The K_m values were (24±0.05),(148±0.09) and (110±0.03)μmol/L and the V_ max values were (60±0.21),(48±0.02) and (34±0.02)μmol·g -1 ·min -1 for quercetin,isorhamnetin and kaempferol,respectively. The IC_ 50 of nifedipine,propafenone,ipriflavone and diphenytriazol on flavonoids metabolism were 54～70,69～122,85～98 and 210～362 μmol, respectively. The inhibition constants(Ki)of diphenytriazol,propafenone and ipriflavone on quercetin,isorhamnetin and keampferol metabolism were(57.6,50.5,33.1),(33.6,59.5,45.2)and(13.7,24.0,15.7)μg/ml,respectively. The ratio / of the plasma concentration and inhibition constant for propafenone was 0.002～0.003. Conclusion: The metabolic level of quercetin is the strongest among three Ginkgo flavonoids. Nifedipine,propafenone and ipriflavone inhibite the metabolism of quercetin,isorhamnetin and keampferol at different levels. Because of the interaction between Ginkgo flavonoids with nifedipine,caution must be taken when two drugs are used together clinically.

关 键 词：黄酮类 药代动力学 黄酮类 代谢 普罗帕酮 硝苯地平 地非三唑 药物相互作用 

分 类 号：R969.2[医药卫生—药理学]