肾病综合征条件下肾有机阴离子转运体介导的雷公藤多苷与袢利尿剂的相互作用研究

In Chinese clinical therapy, Tripterygium glycosides(GTW) and loop diuretics are always used together in nephrotic syndrome for treat proteinuria and edema, in order to delay the progress from NS to renal failure. And GTW is good for treat glucocorticoid resistance nephrotic syndrome. The drug combination presents a favourable prognosis. The main effective ingredients of GTW are eliminated and excreted by kidney, and can inhibit the kidney OATs. All the loop diuretics are typical substrates of kidney OATs, and they can strongly stimulate the kidney excreting xenobiotics. When GTW combines with loop diuretics for the treatment of NS, the drug-drug interaction that GTW may make the loop diuretics more effective and the loop diuretics may accelerate the excretion of GTW, which can decrease the toxicity caused by GTW. This interaction may cause by kidney OATs. With renal disease like renal failure, the kidney organic anion transporters (OATs) will be inhibited and decreased. We predict that in a condition of NS, the effect-enhancing and toxicity-reducing of drug combination between GTW and loop diuretics may enhance..In this study, the NS rats will be modeled, and the mRNA expression of their kidney OATs will be determined and make a comparison to the healthy rats. We also need to study the pharmacokinetics and pharmacodynamics of GTW/furosemide single/combine use in the NS model rats/the healthy rats. And then, we will characterize the actual impact on kidney OATs of GTW by vitro cell test. Base on the results of in vivo and in vitro research, the aim of this study is to certificate the effect-enhancing and toxicity-reducing of drug combination between GTW and loop diuretics use in NS treatment through kidney OATs..According to the real therapeutic regimen in Chinese clinic, this study will use PK-PD research in vivo and cell test in vitro to reveal the mechanism of drug interaction between GTW and loop diuretics through kidney OATs suppression in NS. Aim at promoting rational drug use in the clinic.

雷公藤多苷片（GTW）常用于肾病综合征（NS）特别是糖皮质激素抵抗NS的蛋白尿治疗，袢利尿剂治疗水肿，延缓NS发展为肾衰进程，两药合用未见相关不良反应报道。雷公藤成分主经肾消除排泄，并可抑制肾有机阴离子转运体（OATs），加速肾排泄的袢利尿剂均为肾OATs典型底物，推测二者合用可增强利尿剂作用并减轻雷公藤毒副作用。肾衰等肾脏疾病会导致肾OATs表达下调，推测NS下，两药合用减毒增效效果将提升。.本项目拟考察NS大鼠的肾OATs下调情况，研究正常/NS大鼠体内GTW与袢利尿剂呋塞米单独/合用后的药动学、药效学特征，辅以体外细胞实验明确GTW确切成分对OATs的作用特点，验证GTW与呋塞米联用减毒增效作用及治疗NS基于OATs下调增强相互作用的机制。.本研究基于临床实际，以体内PK-PD结合体外细胞实验验证GTW与袢利尿剂合用时基于NS肾OATs下调发生的增强协同作用，为临床合理用药提供依据。

背景：临床常使用雷公藤多苷片（Tripterygium glycosides，GTW）缓解大量蛋白尿症状，以呋塞米（furosemide，FSM）为代表的袢利尿剂也常同时应用以治疗水肿，二药在治疗肾病综合征（Nephrotic Syndrome，NS）时会发生联用。该两类药物可能通过肾脏有机阴离子转运体（OAT）发生相互作用。.内容：进行肾病综合征（NS）大鼠造模。展开两药药动学研究：模型大鼠口服雷公藤多苷片和呋塞米单独及合并用药后的药动学研究；累积给药GTW2周后，再口服给药FSM药动学研究，累积给药GTW+FSM2周药动学研究。健康大鼠口服GTW和FSM单独及合并用药后药动学研究；累积给药GTW2周后再口服给药FSM的药动学研究；累积给药GTW+FSM2周药动学研究。模型大鼠与健康大鼠肾切片OATs的mRNA及蛋白表达差异。.结果：肾病综合征条件下，模型动物肾脏中的有机阴离子转运体OAT1~3会显著下调。经临床剂量雷公藤多苷片累积治疗后，OAT表达有所回升。两药合用或累积使用雷公藤多苷片，在健康大鼠体内会诱导OAT1~3的表达上调。健康和疾病状态下，雷公藤多苷片和呋塞米各自单用的药动学特征会发生变化，呋塞米暴露降低，而雷公藤多苷片的主要成分暴露显著升高。两药合用时，呋塞米会降低雷公藤主要成分的暴露。健康状态下，合用两药会降低呋塞米的血浆暴露程度，但5倍剂量雷公藤与呋塞米连续合用则可提升呋塞米的血浆暴露。在疾病状态下，经雷公藤累积治疗后的大鼠合用呋塞米，呋塞米比不经治疗组暴露有所提升，但不及健康组。雷公藤多苷片对肾病综合征大鼠具有治疗效果，并能一定程度上恢复肾脏有机阴离子转运体的活性。.意义：本研究证明，在肾病综合征情况下，肾脏有机阴离子转运体确会下调，经雷公藤多苷片治疗后能够有所回升。且雷公藤多苷片与呋塞米合用会发生相互作用，在临床使用时需注意。

内容获取失败，请点击重试