本文選題：LLDT-8 + 藥物代謝動(dòng)力學(xué)��； 參考：《華東理工大學(xué)》2014年碩士論文

【摘要】：類風(fēng)濕性關(guān)節(jié)炎是一種慢性全身性自身免疫性疾病,多數(shù)免疫抑制劑對(duì)機(jī)體的作用缺乏特異性和選擇性,毒副作用大使廣泛使用受到限制。(5R)-5-羥基雷公藤內(nèi)酯醇(商品名：雷騰舒；簡稱：LLDT-8)是由上海醫(yī)藥集團(tuán)股份有限公司中央研究院開發(fā)的用于治療類風(fēng)濕性關(guān)節(jié)炎的一類創(chuàng)新藥物,臨床上擬將其與甲氨蝶呤聯(lián)合用藥以治療類風(fēng)濕性關(guān)節(jié)炎,本論文主要對(duì)LLDT-8的藥物代謝性質(zhì)進(jìn)行了系列研究。 研究結(jié)果顯示：LLDT-8為高透過性的藥物,不同濃度的Papp相差不明顯,外排比接近于1,并且隨著給藥濃度的增加通透量呈線性增加,初步判斷LLDT-8為被動(dòng)擴(kuò)散。LLDT-8在大鼠的十二指腸、空腸、回腸和結(jié)腸均有較高的吸收,同時(shí)給予甲氨喋呤后,LLDT-8在除十二指腸以外的腸段的吸收率均有小幅下降,但無顯著性差異。LLDT-8對(duì)人肝微粒體亞型(CYP3A4、CYP2D6、CYP1A2、CYP2C9和YP2C19)無明顯的抑制或誘導(dǎo)作用(在0.1～10μM濃度范圍內(nèi)),并且甲氨蝶呤不是CYP450酶的底物也不是抑制劑,因此LLDT-8和這幾個(gè)CYP酶亞型抑制劑和誘導(dǎo)劑發(fā)生藥物藥物相互作用的可能性很小。此外,LLDT-8不是P-GP的潛在底物和抑制劑,亦不是BCRP的底物但對(duì)BCRP有抑制,由于人體內(nèi)難達(dá)到抑制濃度,所以LLDT-8與P-GP和BCRP的抑制劑和底物發(fā)生相互作用的可能性低。 總之,LLDT-8在體內(nèi)吸收良好,為全腸段吸收,同時(shí)甲氨喋呤與其聯(lián)合用藥發(fā)生藥物-藥物相互作用的可能性很低,臨床聯(lián)合用藥治療類風(fēng)濕性關(guān)節(jié)炎有一定的理論基
[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.
【學(xué)位授予單位】：華東理工大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：TQ460.1;R969.2

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