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系統識別號 U0026-0307201311422200
論文名稱(中文) 以 etanercept 為例,探討在大鼠上小分子藥物對於蛋白質藥物分布的影響
論文名稱(英文) Effects of Small-Molecule Drugs on Etanercept Disposition in Rat model
校院名稱 成功大學
系所名稱(中) 臨床藥學與藥物科技研究所
系所名稱(英) Institute of Clinical Pharmacy and Pharmaceutical sciences
學年度 101
學期 2
出版年 102
研究生(中文) 周昱全
研究生(英文) Yu-Chuan Chou
學號 s66004050
學位類別 碩士
語文別 中文
論文頁數 55頁
口試委員 指導教授-黃金鼎
口試委員-周辰熹
口試委員-俸清珠
中文關鍵字 蛋白質藥物  藥物分布  藥物交互作用 
英文關鍵字 therapeutic protein  drug distribution  drug interaction 
學科別分類
中文摘要 研究背景
近年來隨著生技產業的蓬勃發展,蛋白質治療藥物已成為越來越重要的藥物治療方式。在臨床治療合併用藥上,蛋白質治療藥物的加入,需要更新且更深入的思惟,來評估藥物併用的安全性和有效性,然而在文獻上,這類的研究卻非常有限。從藥物動力學的觀點,蛋白質藥物有著與傳統小分子藥物截然不同的特性,例如在藥物分佈上,這樣一個極大分子量、高水溶性的物質,在藥物擴散分佈上是相對緩慢的,因為這些大分子被認為只能透過有限度地血管內擴散 (diffusion)和對流運輸 (convection),來達到藥物吸收和穿透至組織中。
研究目的
本研究從臨床上藥物治療的角度上出發,以etanercept為例,探討在類風性關節炎 (Rheumatoid Arthritis, RA)的治療上較常與之併用的抗發炎或是具有疾病修飾的(Disease Modifying Anti-Rheumatic Drug, DMARDs)小分子藥物,例如NSAIDs、methotrexate、steroids,是否對於該蛋白質藥物,在藥物分佈上造成影響,並探討其藥物交互作用可能的藥理機轉。
研究方法
建立評估小分子藥物與蛋白質藥物交互作用的大鼠模式,大鼠腹腔投與單劑量小分子藥物後,靜脈注射etanercept,收集六小時內血漿及皮膚組織液,並利用專一性酵素免疫分析法 (enzyme-linked immunoassay, ELISA)來定量血中及皮膚組織液中etanercept的濃度。觀察比較合併藥物對於etanercept在血中和皮膚中濃度與其他藥動參數的影響。
研究結果
前投與單劑量methylprednisolone、indomethacin和methotrexate,皆有降低靜脈注射etanercept的血中濃度曲線下面積(AUC)的趨勢,且顯著的差異是在於產生較短的etanercept的分佈相半衰期; 但在皮膚組織上,相較於對照組,indomethacin和methotrexate皆不會造成etanercept分佈到皮膚的差異; methylprednisolone會增加etanercept分佈到皮膚組織的量,且若多劑量維持高濃度的methylprednisolone,則會使分佈到皮膚組織的量產生更顯著的增加。
研究結論
Methylprednisolone與etanercept併用的結果,在健康大鼠身上可顯著增加etanercept的藥物組織分佈。本研究建立了一套直接測定組織藥物濃度的動物模式,評估RA蛋白質治療藥物與小分子藥物之間的交互作用,此模式將來也可應用探討其他適應症的治療藥物,是否也有影響蛋白質藥物分佈的潛在交互作用,對於使用蛋白質治療的患者,在臨床共病症的藥物選擇上提供更多的資訊。
英文摘要 There have been significant advancements in the development of therapeutic proteins over past decades. It is estimated that more than 500 therapeutic proteins are presently in development, and approximately 30 therapeutic proteins currently are approved by the U.S. Food and Drug Administration (FDA). With increasing use of therapeutic proteins in poly-pharmacy settings calls for more in-depth understanding of biological interactions that can lead to toxicity or loss of pharmacological effect. However, in literature, such research is very limited. For large, polar substances such as mAbs, diffusion across vascular endothelial cells is very slow, and convection is believed to be the primary mechanism responsible for
the transport of antibody from blood fluid to interstitial fluids of tissue.
We investigated the effects of small molecule drugs, which were frequently used in the treatment of rheumatoid arthritis, on drug distribution kinetics of etanercept in a rat model. Rat were given etanercept intravenously follow by single dose of small molecule drugs intraperitoneally. After six hours, serum and skin tissue fluid concentration were measured by validated specific enzyme-linked immunoassay. Our results showed that pre-administered methylprednisolone, indomethacin and methotrexate reduce serum area under the curve (AUC) of etanercept with a shorter distribution half-life compared to control group. But in skin tissue, only methylprednisolone group has significant increase in the amount of etanercept. If we used multiple doses to maintain a high concentration of methylprednisolone, the distribution amount of etanercept would increase more.
In this study, we found co-administration of methylprednisolone and etanercept resulted in significant increase in tissue distribution of etanercept. We established a direct determination of tissue drug concentrations on rat skin to evaluate the effects of small molecule drugs on distribution kinetics of RA therapeutic proteins. This approach may also be applied in other comorbidity medications with some pharmacological interaction potentials and provide more information of drug choice
for patient under protein therapy.
論文目次 中文摘要 I
Abstract III
致謝 V
目錄 VII
表目錄 IX
圖目錄 X
縮寫檢索表 XI
第一章 緒論 1
第一節 研究背景 1
第二節 文獻回顧 1
第三節 研究目的 8
第二章 研究材料及儀器 9
第一節 研究材料 9
壹、 實驗動物 9
貳、 試驗用藥品 9
參、 其他化學藥品與試劑 9
肆、 單株抗體 11
伍、 其他器材 11
第二節 研究儀器 12
第三節 藥動分析與統計軟體 12
第三章 研究設計與方法 13
第一節 動物實驗設計 13
壹、 藥品溶液配製: 13
貳、 Etanercept藥物交互作用實驗 14
第二節 血漿及皮膚組織檢品處理 15
壹、 血液檢品處理 15
貳、 皮膚檢品處理 15
第三節 Etanercept含量分析方法 16
壹、 酵素連結免疫吸附法(Enzyme - linked immunosorbent assay) 16
貳、 Etanercept檢量線及檢品配製 18
參、 ELISA 測定步驟 20
第四節 Etanercept標準品分析方法確效(準確度與精密度) 21
第五節 藥物動力學參數分析與統計分析 21
第四章 研究結果 22
壹、 Etanercept分析法之檢量線和確效 22
貳、 Etanercept分析法之基質效應測試(Matrix effect) 22
參、 小分子藥物對Etanercept 血漿中濃度和藥動參數的影響 23
肆、 小分子藥物對Etanercept在皮膚組織中濃度和藥動參數的影響 24
伍、 小分子藥物對Etanercept組織/血液分配係數的影響 25
第五章 討論 26
第六章 結論 31
參考文獻 32
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