基因多态“网络”下丹参素对他汀类药物转运、代谢影响的分子机制及其与调脂效应的关联研究

The statins is an HMG-CoA reductase inhibitor with exactly clinical efficacy. Transporter, metabolic enztme and effect target gene polymorphism significantly affect the lipid lowering effect of statins. When combined with Danshen agents, statin's lipid lowering effect was significantly enhanced. Our preliminary studies found that Danshensu was a substrate of OATP1B1 and can inhibit the transporting of statins,resulting in the decline of drug concentration in target site.But whether reduce the lipid lowering effect of stains or not is unknown. Data exhibit that Danshensu can inhibit the activity of CYP2C9, which maybe reduce the metabolism of statins, and thus improve the efficacy of stains is not clear. As for OATP1B1, CYP2C9, ApoE and HMG-GoA reductase gene mutation, the relationship of Danshensu effect on statins drug transport, metabolism and efficacy of lowe rlipid is more worthy of attention. Therefore, this research is aimed to: ①explore the molecular mechanism of Danshensu effect on statins transporting and metabolism under gene mutation, by constructing different gene plasmid; ②construct the gene polymorphism network by population pharmacokinetics-pharmacology linked model under statins combination with Danshensu; and clarify the effect molecular mechanism of Danshensu on statins transporting, metabolism and efficacy and its internal correlation under polymorphism network; create a new idea for correlation study with muti-pathway、muti-target under polymorphism network.

他汀类药物是临床疗效确切的HMG-GoA还原酶抑制剂，其转运、代谢和效应靶点的基因多态性明显影响调脂效应，而联用丹参制剂后他汀类药物调脂效果却显著增强。我们前期研究发现丹参素是OATP1B1底物，可抑制他汀类药物转运，造成作用靶点药物浓度下降，是否因此减低疗效不得而知。有资料显示丹参素能抑制CYP2C9酶活性，此作用是否降低他汀类药物代谢因而提高疗效尚不清楚。至于丹参素在OATP1B1、CYP2C9、ApoE及HMG-GoA还原酶基因突变时对他汀类药物转运、代谢的影响与疗效有何关联更值得关注。因此本课题拟①通过构建不同基因质粒，研究基因突变下丹参素对他汀类药物转运、代谢的影响及分子机制；②运用联合用药群体PK-PD链式模型，构建基因多态"网络"，阐明多态"网络"下丹参素对他汀类药物转运、代谢与疗效的影响及其内在关联性；为拓展联合用药在基因多态"网络"下多通道、多靶点的关联研究增添新思路。

他汀类药物是临床疗效确切的 HMG-GoA 还原酶抑制剂，其转运、代谢和效应靶点的基因多态性明显影响调脂效应，联用丹参制剂后他汀类药物调脂效果却显著增强。我们研究发现丹参素是 OATP1B1 底物，可抑制他汀类药物转运，造成作用靶点药物浓度下降，进一步研究发现丹参素对不同基因型 OATP1B1代谢他汀类药物影响不同。研究发现不同基因型重组酶的代谢活性有差别，丹参组分对不同基因型重组酶代谢氟伐他汀的抑制能力上亦有差别，这也可能是由于突变导致酶的空间构象发生改变，影响了底物或抑制剂与酶活性位点的结合。ApoE基因突变不仅直接引起LDLR结合力的降低，可能还通过细胞内的某些途径直接又或间接的减低HMG-CoA还原酶的表达量，从而加强氟伐他汀降脂疗效。本研究建立的氟伐他汀群体药代动力学模型发现，OATP1B1 388A>G、OATP1B1 521T>C、合并丹参素给药、年龄对氟伐他汀的PPK参数有显著影响，OATP1B1 388位点突变降低清除率，合并丹参素给药升高清除率，OATP1B1 521位点突变降低分布容积，年龄越大分布容积越大。本研究阐明多态“网络”下丹参素对他汀类药物转运、代谢与疗效的影响及其内在关联性，为拓展联合用药在基因多态“网络”下多通道、多靶点的关联研究增添新思路。