（5R）-5-羟基雷公藤内酯醇的吸收机制和与甲氨蝶呤联合用药的药物—药物相互作用研究

发布时间：2018-04-19 22:33

本文选题：LLDT-8 + 药物代谢动力学　；参考：《华东理工大学》2014年硕士论文

【摘要】：类风湿性关节炎是一种慢性全身性自身免疫性疾病,多数免疫抑制剂对机体的作用缺乏特异性和选择性,毒副作用大使广泛使用受到限制。(5R)-5-羟基雷公藤内酯醇(商品名：雷腾舒；简称：LLDT-8)是由上海医药集团股份有限公司中央研究院开发的用于治疗类风湿性关节炎的一类创新药物,临床上拟将其与甲氨蝶呤联合用药以治疗类风湿性关节炎,本论文主要对LLDT-8的药物代谢性质进行了系列研究。研究结果显示：LLDT-8为高透过性的药物,不同浓度的Papp相差不明显,外排比接近于1,并且随着给药浓度的增加通透量呈线性增加,初步判断LLDT-8为被动扩散。LLDT-8在大鼠的十二指肠、空肠、回肠和结肠均有较高的吸收,同时给予甲氨喋呤后,LLDT-8在除十二指肠以外的肠段的吸收率均有小幅下降,但无显著性差异。LLDT-8对人肝微粒体亚型(CYP3A4、CYP2D6、CYP1A2、CYP2C9和YP2C19)无明显的抑制或诱导作用(在0.1～10μM浓度范围内),并且甲氨蝶呤不是CYP450酶的底物也不是抑制剂,因此LLDT-8和这几个CYP酶亚型抑制剂和诱导剂发生药物药物相互作用的可能性很小。此外,LLDT-8不是P-GP的潜在底物和抑制剂,亦不是BCRP的底物但对BCRP有抑制,由于人体内难达到抑制浓度,所以LLDT-8与P-GP和BCRP的抑制剂和底物发生相互作用的可能性低。总之,LLDT-8在体内吸收良好,为全肠段吸收,同时甲氨喋呤与其联合用药发生药物-药物相互作用的可能性很低,临床联合用药治疗类风湿性关节炎有一定的理论基
[Abstract]:Rheumatoid arthritis is a chronic systemic autoimmune disease, and most immunosuppressants lack specificity and selectivity. The toxic and side effects ambassador is a class of innovative drugs for the treatment of rheumatoid arthritis developed by Academia Sinica of Shanghai Pharmaceutical Group Co., Ltd. (trade name: Lei Tengshu; abbreviated as "1: LLDT-8"), which is widely used in restricted use of .r-5r-5-hydroxytriptolide (trade name: Lei Tengshu; abbreviated as "WLLDT-8"). In order to treat rheumatoid arthritis (RA) with methotrexate (MTX), the metabolic properties of LLDT-8 were studied in this paper. The results showed that: LLDT-8 was a highly permeable drug, the difference of Papp at different concentrations was not obvious, the efflux ratio was close to 1, and the permeability increased linearly with the increase of drug concentration. It was preliminarily judged that LLDT-8 was passive diffusion. LLDT-8 was the duodenum of rats. The absorption rate of LLDT-8 in jejunum, ileum and colon was decreased slightly after methotrexate administration. But there was no significant difference. LLDT-8 had no significant inhibition or induction effect on CYP2D6, CYP2C9 and YP2C19, and methotrexate was not a substrate for CYP450, nor was methotrexate an inhibitor. Therefore, the drug interaction between LLDT-8 and these CYP isoforms inhibitors and inducers is very small. In addition, LLDT-8 is not a potential substrate and inhibitor of P-GP, nor is it a substrate of BCRP, but it inhibits BCRP. Because it is difficult to reach the inhibitory concentration in human body, LLDT-8 is less likely to interact with inhibitors and substrates of P-GP and BCRP. In short, LLDT-8 absorbs well in vivo and is absorbed in whole intestine. At the same time, the possibility of drug-drug interaction between methotrexate and LLDT-8 is very low. There is a certain theoretical basis for the treatment of rheumatoid arthritis with clinical combined use of LLDT-8.
【学位授予单位】：华东理工大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：TQ460.1;R969.2

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