抗艾滋病中药复方ZYSH对茚地那韦的代谢性增效作用  

Enhanced anti-HIV efficacy of indinavir by metabolic interactions with the traditional Chinese medicine prescription ZYSH

作　　者：毛玉昌[1,2] 孙易 侴桂新[1,3] 胡卓汉[1,2] 

机构地区：[1]上海中医药大学中药研究所,上海201203 [2]瑞德肝脏疾病研究(上海)有限公司,上海201203 [3]上海中药标准化研究中心,上海201203

出　　处：《中国新药杂志》2012年第24期2875-2880,共6页Chinese Journal of New Drugs

基　　金：国家"重大新药创制"科技重大专项(2008ZX10005-005)

摘　　要：目的:本文研究抗艾滋病中药复方ZYSH对人肝微粒体CYP3A4的活性抑制和对茚地那韦体外代谢的增效作用,及其对茚地那韦在SD大鼠体内暴露量的增加。方法:中药复方ZYSH总浸膏用磷酸缓冲液(PBS)稀释后与混合人肝微粒体预孵育15 min,加入探针底物睾酮和辅酶β-NADPH孵育30 min,用LC-MS/MS定量检测6β-羟基睾酮的生成,计算ZYSH对CYP3A4的抑制率(IC50)。5 mg.mL-1和10 mg.mL-1的ZYSH在与人肝微粒体共同孵育15 min后加入茚地那韦和β-NADPH分别孵育0,15,30,60,90和120min,检测复方对茚地那韦体外代谢的影响。SD大鼠体内灌胃给予ZYSH 7 d,再经灌胃给予茚地那韦,检测茚地那韦的血药浓度,观察复方ZYSH对茚地那韦的体内暴露的影响。结果:复方ZYSH能明显抑制CYP3A4的活性,IC50为3.21 mg.mL-1。5 mg.mL-1和10 mg.mL-1的ZYSH在体外能明显抑制茚地那韦的代谢,其t1/2由47.5 min变为184和1 404 min,微粒体对茚地那韦的固有清除率由对照组的36.6 mL.min-1.kg-1分别改变为9.4和1.2 mL.min-1.kg-1。灌胃给予ZYSH 7 d后茚地那韦在SD大鼠体内AUC明显增加,为对照组的2.1倍。结论:复方ZYSH能够抑制人肝微粒体CYP3A4的活性,通过代谢性相互作用减缓茚地那韦的体外代谢,增加大鼠体内暴露量。Objective： To evaluate the effect of the anti-HIV traditional Chinese medicine prescription ZYSH on CYP3A4 activity of human liver microsomes,indinavir metabolic enhancement in vitro,and the increased exposure content of indinavir in SD rats.Methods： The ZYSH extract was diluted in PBS and pre-incubated with human liver microsomes for 15 min,and incubated with testosterone and β-NADPH for 30 min.The enzyme activities and formation of 6β-OH testosterone were quantified by LC-MS/MS.Inhibition potentials（IC50） were calculated.The extract（5 and 10 mg·mL-1） was pre-incubated with pooled human liver microsomes for 15 min,and further incubated with indinavir and β-NADPH for 0,5,15,30,60,and 120 min.Half-life（t1/2） of indinavir parent was calculated and effects of ZYSH on metabolism of indinavir were evaluated in SD rats.Rats were intragastrically administered with ZYSH for 7 days,and then indinavir was given.Plasma concentration of indinavir was quantified to calculate the plasma exposure.Results： ZYSH obviously inhibited the CYP3A4 activity and the IC50 value was 3.21 mg·mL-1;therefore it also inhibited the metabolism of indinavir in vitro.The t1/2 of indinavir was prolonged from 47.5 min to 184 and 1 404 min after incubated with ZYSH at concentrations of 5 and 10 mg·mL-1;while the intrinsic clearance reduced from 36.6 mg·mL^-1kg^-1 to 9.4 and 1.2 mg·mL^-1kg^-1,respectively.The AUC of indinavir in SD rats treated with ZYSH for 7 days were 2.1 folds of the control rtas treated with saline.Conclusion： ZYSH can slow down metabolism of indinavir through inhibiting the enzyme activity of CYP3A4 in human liver microsomal in vitro and may increase plasma exposure in SD rats through metabolic enhancement.

关 键 词：艾滋病 中药复方 茚地那韦 CYP3A4 代谢性相互作用的增效 

分 类 号：R978.7[医药卫生—药品] R969.1[医药卫生—药学]