抗血管性痴呆益气活血复方与他汀的复杂性中西药相互作用机制解析及合理用药研究

Combined prescription of traditional Chinese medicines（TCMs）and synthetic drugs is a significant character of clinic treatment in our country. However, insufficient investigation on pharmacokinetic mechanism of induced herbal-drug interactions (HDI), leads to great danger of toxic response or treatment failure. The difficulty focus on the complex chemical contents of TCMs and the lack of clinic-applicable data is the most outstanding problem in current situation of HDI. During the treatment of vascular dementia (VD), concomitant medication of TCMs with lipid-lowing drugs of statins has become a regular therapeutic regimen and atorvastatin(AS) is of the most extensively prescribed. A compound TCM Saiuotong (SLT) has been proved efficacious for curing VD in accordance with qi deficiency blood stasis syndrome by previous investigation. Nevertheless，a significant HDI has been observed that SLT reduced systemic exposure of atorvastatin dramatically in VD patients after successive medication in our former study. The HDI is supposed to be the typical complex herb-drug interaction because of the multi-constituents of SLT and multiple metabolic enzymes and transporters mediated PK process of AS. The further research will be conducted by the combination of in vivo and in vitro researches to figure out the effect rules of the HDI and their relationship with efficacy and security of AS as well as constituents of SLT responsible of disturbing the PK of AS and enzymes/ transporters they targeted firstly. More rational concomitant regimen of SLT and statins will be designed based on the clarified mechanism of HDI thereafter. The rationality of the regimen will be verified by pre-clinical tests and proved by clinical trials on patients finally. The study aims to offer scientific reference during the integrative therapy of VD in clinic and explore the applicable research mode of HDI going through clinical observation- mechanism clarification –clinic application in line with the properties of TCMs.

对中西药相互作用（HDI）研究的不足是引发药源性毒副作用或治疗失败的巨大隐患。中药复杂的化学组成是HDI研究中主要难点，临床适用性研究的匮乏是当前最突出的问题。血管性痴呆（VD）的中西医结合治疗中，合并预防脑卒中发生的他汀类降血脂药已成为基本用药模式。既往研究表明益气活血复方塞络通(SLT)有良好抗VD疗效，但前期研究发现联用SLT使阿托伐他汀（AS）在患者体内血药浓度大幅降低。鉴于SLT的复方化学组成及多代谢酶/转运体联动下的AS药动特征，两药联用产生了典型的复杂性HDI。课题拟通过系统的体内与体外研究，解析SLT-AS间复杂性HDI的作用靶代谢酶和转运蛋白及作用来源成分、阐明其作用规律及与药效和安全性的关系，进而依据作用机理制定SLT与他汀的合理用药方案并进行临床验证。课题旨在为VD中西医结合治疗提供科学依据，并探索建立符合中药特点的HDI临床发现-基础研究-临床指导的贯通式研究模式。

中西药相互作用（HDI）研究的不足是引发药源性毒副作用或治疗失败的巨大隐患。前期研究发现联用SLT使阿托伐他汀（AT）在VD患者体内血药浓度大幅降低。课题通过深入的体内和体外研究，解析SLT-AS间复杂HDI的作用机制及来源。.SLT与AT合用在大鼠体内的药代动力学相互作用结果显示单次或连续灌胃SLT表现出升高或降低AT的生物利用度两种不同相互作用方向。针对代谢酶机制的解析结果表明SLT对AT代谢酶CYP3A存在活性抑制和蛋白表达诱导作用，综合作用结果表现出SLT对CYP3A活性的抑制。此外SLT能够上调参与AT葡糖醛酸化的UGT1A1的mRNA的表达。SLT对转运体的影响表现为可同时诱导大鼠肝脏和肠道多种相关转运体的表达，其中对外排转运体MDR1的显著诱导作用最强。采用专一MDR1底物药的实验确证了该机制是造成AT生物利用降低的主要影响因素。高脂模型大鼠结果表明SLT自身具有一定的降脂作用，与AT合用不影响AT的降脂疗效。.在此基础上课题开展了SLT与AT合用的临床研究。与临床前相似，合用可在单剂量和连续服用下对健康人产生不同的影响，且在患者中长期给药下会引起AT血浆暴露水平较大幅度的下降。采用多种人源细胞系进行进一步的机制分析表明SLT可抑制肠道摄取转运体OATP2B1、外排转运体MDR1和,MRP2，并可显著诱导MDR1，因此可在不同浓度下以及在肠道不同部位对吸收显示不同的综合效果。拆方研究发现西红花是主要影响来源。基于临床的in vitro研究也表明对MDR1的诱导可能是降低他汀体内暴露的主要原因。研究提示可利用SLT对转运体的双向调控特点，通过调整SLT与AT的服药间隔减轻HDI。此外选择吸收过程中转运体参与度低的他汀HDI更弱。研究揭示的SLT-AT相互作用机制适用于与其他有共同PK通路药物的联用指导，并为含有同组分药的其他中药制剂的合并用药提供科学依据。