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系統識別號 U0026-1108201711065600
論文名稱(中文) Lurasidone在大白鼠體內藥物動力學與交互作用
論文名稱(英文) Pharmacokinetics and drug interactions of Lurasidone in rats
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 105
學期 2
出版年 106
研究生(中文) 謝光俞
研究生(英文) Kuang-Yu Hsieh
學號 S66041060
學位類別 碩士
語文別 中文
論文頁數 101頁
口試委員 指導教授-周辰熹
口試委員-蔡瑞真
口試委員-洪欣儀
中文關鍵字 lurasidone  mosapride  細胞色素3A  藥品交互作用 
英文關鍵字 lurasidone  mosapride  CYP3A  drug interactions 
學科別分類
中文摘要 研究背景:
Lurasidone為非典型抗精神病藥,於2011年在美國上市,現今已核准的適應症包括第一型躁鬱症相關的重型憂鬱症發作、成人精神分裂症。Lurasidone主要是經由肝臟CYP3A4酵素所代謝,代謝後形成具活性的代謝物ID-14283和ID-14326及不具活性的主要代謝物ID-20219和ID-20220。CYP酵素的抑制、誘導常是藥物之間產生交互作用的重要因素,進而導致藥品的療效不如預期抑或增加毒性、副作用的發生風險。由於lurasidone相較於其他非典型抗精神病藥品有較少的副作用,在臨床治療上具有相當的地位。除了西藥之外,有不少病患會同時選擇中藥或是食療來治療失眠或是情緒相關的慢性疾病,而部分中藥材中的成分也常與CYP3A酵素的代謝相關。關於lurasidone與中藥或食物的交互作用的研究目前並不多見,值得進一步研究。
胃腸蠕動促進劑mosapride主要經由CYP3A所代謝,於先前的相關研究中發現,在大白鼠動物模式以靜脈注射或口服給予mosapride後,分別可觀察到肝臟及腸道中CYP3A酵素含量與mosapride清除率成高度相關性,反應出mosapride可作為CYP3A體內探針性試藥的可行性。
研究目的:
本研究主要目的是利用大白鼠動物模式,探討lurasidone在大鼠體內的藥物動力學,並進一步研究代謝酵素CYP3A對lurasidone藥動學及藥物交互作用的影響。同時以mosapride當作CYP3A活性探針實際應用於lurasidone清除率的評估。為此本研究也開發靈敏的高效液相層析法,來定量血漿檢品中的lurasidone與相關代謝物以進行其藥動參數的評估。

研究方法:
以靜脈注射給予lurasidone,觀察其在大白鼠的藥品動態學。在探討應用mosapride預測lurasidone清除率的實驗中,大白鼠控制組不加處置,或以抑制劑ketoconazole及誘導劑dexamethasone調節CYP3A的含量及活性,再同時由靜脈給予mosapride和lurasidone,研究mosapride在這些條件下對於lurasidone清除率評估的應用性。在口服交互作用試驗中,利用口服投藥方式給予中藥五味子或蔓越莓汁後,接著再口服或靜脈投予lurasidone,探討其交互作用機制。
研究結果:
已成功開發靈敏且能夠同時分析生物體液中的lurasidone與其代謝物的液相層析方法且實際應用至大白鼠體內動力學研究。當給予CYP3A抑制劑ketoconazole後,lurasidone及mosapride之清除率皆顯著減低。給予CYP3A誘導劑dexamethasone後,lurasidone與mosapride之清除率無顯著差異。本實驗也證實了透過有限採樣法,mosapride的單點血中濃度能夠有效地評估其本身的清除率以及lurasidone清除率。當口服五味子30分鐘後再口服lurasidone會明顯增加lurasidone血中濃度曲線下面積(AUC)並具顯著差異(p<0.05);然而,口服五味子2小時及12小時後再口服lurasidone的組別,雖有增加其血中濃度的趨勢,但AUC與控制組無顯著差異。口服蔓越莓汁30分鐘後再口服lurasidone亦有增加其AUC但與控制組並具顯著差異(p<0.05),另外,年齡較大且體重較重的組別中蔓越莓汁對於lurasidone的影響較不明顯,AUC無顯著差異。而口服五味子或蔓越莓汁對靜脈注射lurasidone於藥動參數皆無顯著影響。
研究結論:
以靜脈注射方式投予lurasidone與mosapride後,兩者的清除率在控制、抑制、誘導組呈現正相關。利用mosapride單點的血中濃度也可以對lurasidone清除率有相當程度的預測。在口服大白鼠體內藥物交互作用之研究中,口服中藥五味子及蔓越莓汁後30分鐘內若口服lurasidone則會顯著影響其血中濃度,若五味子投藥間隔時間為2、12小時則無顯著差異,顯示五味子對於CYP3A酵素的影響效力會隨時間減弱;而體重與年齡對於蔓越莓汁抑制大鼠CYP3A酵素之效果,隨體重及年齡增加而降低。另外,由靜脈注射組別的結果顯示,五味子與蔓越莓汁對於CYP3A酵素的抑制效果僅限於腸道並不影響肝臟的酵素活性。
英文摘要 INTRODUCTION
Lurasidone is a novel atypical antipsychotic drug that was recently approved for the treatment of schizophrenia and bipolar depression by the the Food and Drug Administration of United States. Lurasidone has potent blocking activities for the dopamine D2 and serotonin 5-HT2A receptors, but weak or negligible actions for histamine H1, acetylcholine M1 receptors. Based on the mechanism of action, lurasidone which was associated with less weight gain, sedative effects and anticholinergic effects, has a better tolerability than the other antipsychotic drugs.
CYP3A isozymes, one of the most important and abundant CYP450 subfamilies in the liver, are the major enzymes that are responsible for the metabolism of lurasidone. Thus, drugs that induce or inhibit CYP3A enzymes would be expected to change the clearance of lurasidone. Currently, more and more patients have taken Chinese herbal drugs or nutraceuticals as complementary and alternative treatment for insomnia or emotion disorders. Among these Chinese herbal drugs, a lot of them are involved in the drug metabolism by CYP3A. To date, research on drug interactions of lurasidone and Chinese herbal drugs or food is rare and worthy of further study.
The use of selected drugs as in vivo CYP3A probes in drug therapy is of great importance. Previous studies have demonstrated that the clearance of a CYP3A substrate mosapride was well correlated with hepatic and intestinal CYP3A contents and reflected the in vivo CYP3A activity. Therefore, mosapride could be a potential CYP3A probe applicable to drug interactions of lurasidone.
PURPOSE
The objectives of this study were to investigate pharmacokinetics and drug interactions of lurasidone in rats. In addition, in vivo CYP3A probe-mosapride was used for measuring hepatic CYP3A activity and evaluating the lurasidone clearance in rats to support the application of mosapride. A new HPLC method for determination of lurasidone in rat plasma was also developed and applied to explore its kinetics.
METHODS
Two sensitive high-performance liquid chromatography (HPLC) methods, one for quantification of lurasidone using delavirdine as an internal standard, the other for simultaneous determination of mosapride, lurasidone and two metabolites of lurasidone in rat plasma were developed. The analytes and internal standards were separated on Thermo Hypurity C18 column (4.6 mm × 250 mm, 5 μm) and protected by an ODS guard column (10 mm × 4 mm, 5 μm). Fluorescence and ultraviolet detectors were used in this study. Since lurasidone has fluorophoric properties, fluorescent detection (FD) was expected to provide an inexpensive, sensitive, and specific detection of lurasidone in biological samples. The two methods have been fully validated in terms of selectivity, linearity, accuracy, precision, stability, matrix effect and recovery. To investigate the applicability of mosapride as a CYP3A probe, each rat was received mosapride and lurasidone simultaneously by iv route in the control group. CYP3A activities of rats were modulated by the pretreatment with ip dexamethasone or iv ketoconazole for the induction and inhibition group, respectively. Co-medication of wu wei zi or cranberry juice with lurasidone via iv and oral routes were employed to investigate potential drug interactions. The plasma concentrations of lurasidone, its metabolites and mosapride were determined by HPLC methods and the kinetics parameters were estimated by compartmental analysis.
RESULTS
The developed HPLC methods were found to be specific, precise and accurate. Calibration curves for lurasidone was constructed over a range of 0.001 μg/mL to 10 μg/mL. The two sensitive HPLC methods were developed and successfully applied to quantify lurasidone and its metabolites in small volume of rat plasma. The disposition kinetics of lurasidone in rats displayed two-compartmental characteristics, with a distribution half-life of 30 minutes and an elimination half-life of 800 minutes. The clearance of lurasidone and mosapride remained unaltered in rats after induction with dexamethasone, but the elimination rate of the metabolites was obviously accelerated. In the presence of CYP3A inhibitor, ketoconazole, clearance of lurasidone and mosapride decreased significantly. Moreover, disposition kinetics of metabolites were changed. Clearance of mosapride and lurasidone can be well predicted by using a single point of plasma concentration of mosapride. When wu wei zi or cranberry juice was orally administered 30 minutes before oral administration of lurasidone, the AUC of lurasidone increased significantly. However, when wu wei zi was orally administered 2 or 12 hours before lurasidone, the AUC of lurasidone showed no significant difference. In the aged group, cranberry juice did not affect the systemic exposure of lurasidone. Interestingly, the iv disposition of lurasidone remained unchanged after oral intake of wu wei zi or cranberry juice.
CONCLUSION
The correlation between the clearances of mosapride and lurasidone supports the applicability of mosapride as an in vivo hepatic CYP3A probe. Mosapride concentration at 90 min after a single intravenous dose was useful in predicting total body clearance of lurasidone. The fact that wu wei zi and cranberry juice affect only the absorption but not disposition kinetics of lurasidone suggested that the interactions were due to inhibition of intestinal but not hepatic CYP3A activity.
論文目次 第壹章 緒論 1
第一節 肝臟細胞色素(Cytochrome P450) 1
一、 分布及特性 1
二、 不同物種間CYP450差異 2
第二節 代謝酵素CYP3A 2
一、 種類及分布 2
二、 個體間活性表現差異 3
三、 酵素受誘導與抑制的作用 3
四、 年齡對於CYP3A酵素的影響 4
第三節 體內CYP3A探針性試藥 5
一、 理想體內探針性試藥條件 5
二、 現行已知的CYP3A體內探針性試藥介紹 6
第四節 Mosapride簡介 8
一、 物化性質 8
二、 作用機轉 8
三、 藥動特性 8
四、 藥物交互作用 12
五、 Mosapride作為探針性試藥的相關研究 12
第五節 Lurasidone 簡介 15
一、 物化性質 15
二、 作用機轉 15
三、 藥動特性 16
四、 藥物交互作用 21
五、 分析方法整理 21
第六節 五味子簡介 23
一、 來源與成份 23
二、 相關文獻 24
第七節 蔓越莓汁簡介 25
一、 來源與成份 25
二、 相關文獻 27
第貳章 研究目的 28
第一節 Lurasidone定量分析方法之開發 28
第二節 Lurasidone在大白鼠體內之藥動學研究 28
第三節 CYP3A活性探針mosapride於lurasidone藥動學之應用 29
第四節 Lurasidone與藥物及食物之交互作用 29
第參章 實驗材料、儀器與方法 30
第一節 實驗材料 30
一、 實驗動物 30
二、 藥品與試劑 30
第二節 實驗儀器 31
一、 紫外光/可見光分光光度計 31
二、 螢光分光光度計 31
三、 高效液相層析系統 31
四、 動物實驗手術及檢品處理 32
五、 繪圖及藥動分析軟體 33
第三節 實驗方法 34
一、 Lurasidone紫外光全光譜與螢光全光譜 34
二、 藥品配製與定量分析 34
三、 Lurasidone在大白鼠之藥物動態試驗 37
四、 實驗設計 40
五、 數據解析 42
第肆章 實驗結果 45
第一節 Lurasidone定量分析方法之開發 45
一、 分析條件開發 45
二、 校正曲線 51
三、 確效評估 54
第二節 Lurasidone在大白鼠體內之藥動學研究 58
一、 Lurasidone分布動態研究 58
二、 Mosapride與lurasidone之藥品動態研究 59
第三節 CYP3A活性探針mosapride於lurasidone藥物動力學之應用 66
一、 Mosapride單點血中濃度與mosapride AUC之相關性 66
二、 Mosapride單點血中濃度與mosapride清除率之相關性 66
三、 Mosapride清除率與lurasidone清除率之相關性 67
四、 Mosapride單點血中濃度與lurasidone清除率之相關性 67
第四節 Lurasidone與藥物及食物之交互作用 69
一、 Lurasidone與中藥五味子之交互作用 69
二、 Lurasidone與蔓越莓汁之交互作用 74
第伍章 討論 81
第一節 Lurasidone定量分析方法之開發 81
第二節 Lurasidone在大白鼠體內之藥動學研究 82
一、 Lurasidone分布動態研究 82
二、 Mosapride與lurasidone之藥品動態研究 82
第三節 CYP3A活性探針mosapride於lurasidone藥物動力學之應用 85
一、 Mosapride單點血中濃度與其AUC之相關性 85
二、 Mosapride單點血中濃度與其清除率之相關性 85
三、 Mosapride清除率與lurasidone清除率之相關性 85
四、 Mosapride單點血中濃度與lurasidone清除率之相關性 85
第四節 Lurasidone與藥物及食物之交互作用 86
一、 Lurasidone與中藥五味子之交互作用 86
二、 Lurasidone與蔓越莓汁之交互作用 88
第陸章 結論 90
參考文獻 92
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