基于代谢酶的复方丹参滴丸合用氯吡格雷协同增效机理研究

Currently, clopidogrel has been commonly used as platelet inhibitor. However, the high incidence of clopidogrel resistance (CR, approximately 5-40 % of patients treated with clopidogrel do not display an adequate anti-platelet response), greatly limited its clinical applications. Non-active carboxylic acid metabolite accumulation is now considered as one of the major reason of occurrence. Compound Danshen Dripping Pills(CDPP)can improve CR, but the specific mechanism is not clear. Previously, we have demonstrated that the elimination of carboxylic acid metabolite from the body could be accelerated by the application of CDPP. and clopidogrel and CDPP were both considered to be beneficial to cardiovascular diseases in clinical and often used in combination. These results indicated that CDPP may decrease in-vivo accumulation of carboxylic acid metabolite via acceleration of its excretion by competing the key enzyme. The effect of CDPP on key metabolic enzymes of clopidogrel activation was firstly investigated by cocktail method. The pharmacokinetics (PK) characteristics of the prototype and the non active metabolic product between clopidogrel alone and in combination with CDPP group were then compared by LC-MS/MS method. The Synergistic anti-platelet effect between clopidogrel alone and in combination with CDPP group was finally investigated. Our project would provide a new methodology for developing the therapy of herbal medicine for CR prevention through PK- pharmacodynamic combination method

氯吡格雷是重要的血小板抑制剂,但临床约5-40%患者发生氯吡格雷抵抗,体内非活性代谢物蓄积是主要原因。临床上,复方丹参滴丸可改善氯吡格雷抵抗已有报道,但机理不清。氯吡格雷为前药,经不同的CYP450亚酶分别代谢为活性和非活性代谢物。我们前期研究证实,联用复方丹参滴丸可减少氯吡格雷非活性代谢物蓄积,而复方丹参滴丸本身具有抗血小板凝聚作用,据此我们推测复方丹参可能通过诱导或抵制了关键的氯吡格雷代谢酶,从而改善氯吡格雷抵抗，协同抗血小板聚集。本课题拟系统研究复方丹参滴丸对关键代谢酶的影响,并比较氯吡格雷单用和合用复方丹参滴丸,氯吡格雷原型和非活性代谢产物的药动学特征,从药物代谢与动力学角度阐明复方丹参滴丸合用氯吡格雷协同增效的机理

心血管疾病是一种发生率和病死率很高的疾病，复方丹参滴丸等中药制剂与氯吡格雷联合应用时可显著增强药效，但其作用机制不清楚。申请人前期研究在大鼠水平证实了联用复方丹参滴丸可减少氯吡格雷非活性代谢物蓄积。本项目将在前期工作基础上，系统研究了复方丹参滴丸对氯吡格雷关键代谢酶的影响,并比较氯吡格雷单用和合用复方丹参滴丸,人参皂苷Rg1、氯吡格雷非活性代谢产物和活性代谢产物氯吡格雷硫醇的药动学特征,以及各组间药效学差异，从药物代谢动力学、药效学角度阐明复方丹参滴丸合用氯吡格雷协同增效的机理。此研究对复方丹参滴丸和氯吡格雷两种药物中西药协同作用机理进行深入研究，将有助于指导临床的个体化和合理化用药，将使更多患者受益，具有一定的学术意义和现实价值。