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系統識別號 U0026-0812200915232589
論文名稱(中文) CYP3A5基因型對不同劑型之鈣離子阻斷劑nifedipine在藥物動力學上之影響
論文名稱(英文) Effects of CYP3A5 genotype on nifedipine pharmacokinetics in different dosage forms
校院名稱 成功大學
系所名稱(中) 藥理學研究所
系所名稱(英) Department of Pharmacology
學年度 97
學期 2
出版年 98
研究生(中文) 陳逸華
研究生(英文) Yi-Hua Chen
電子信箱 s2696103@mail.ncku.edu.tw
學號 s2696103
學位類別 碩士
語文別 中文
論文頁數 62頁
口試委員 指導教授-賴明亮
指導教授-黃金鼎
口試委員-周辰熹
中文關鍵字 劑型  基因型  鈣離子阻斷劑  藥物動力學 
英文關鍵字 nifedipine  CYP3A5 
學科別分類
中文摘要 Cytochrome P450類代謝酵素對體內物質代謝具有相當重要的角色,其中以CYP3A4為主要代謝酵素,但CYP3A5亦有相當程度的貢獻。目前已知CYP3A5基因存有許多單一核苷酸變異(single nucleotide polymorphism, SNP),又以位於內含子3 (intron 3)的g.6986A>G最為廣泛研究,帶有此SNP的allele命名為CYP3A5*3,這個SNP會造成RNA錯誤的splicing,使mRNA不穩定,因此若為CYP3A5*3/*3個體則其CYP3A5表現明顯減少。理論上CYP3A5表現較少(CYP3A5-negative)的個體代謝CYP3A5受質的能力較低,血中受質濃度較高,但綜合許多研究結果發現並非如此。過去文獻指出alprazolam、sirolimus、tacrolimus在CYP3A5*3/*3個體確實有較高的血中濃度,但本實驗室先前研究發現midazolam的藥物動力學於CYP3A5*1/*3與CYP3A5*3/*3個體之間並無明顯差異。推論針對某部分受質,CYP3A5-negative個體在小腸可能有CYP3A4 代償性表現增加的情況。
為了確認腸道中不同部位可能的CYP3A4表現增加情形,我們利用nifedipine兩種不同劑型的藥物進行人體試驗,Adalat為速效劑型,能在腸道前段迅速被吸收,而Coracten為緩釋劑型,預期主要在腸道後段被吸收。試驗依藥物分為兩組,各組含有12位CYP3A5*1/*3及12位CYP3A5*3/*3的健康男性受試者,分別給予單一劑量Adalat 10 mg及單一劑量Coracten 20mg,並抽血分析相關藥物動力學參數。
研究結果顯示在Coracten的試驗中CYP3A5基因型並不影響nifedipine的藥物動力學。然而,在Adalat的試驗中,CYP3A5*3/*3的受試者相較於CYP3A5*1/*3受試者有較低的最大血中濃度(分別為71.5±54.5 ng/mL及128.5±73.8 ng/mL,P=0.04)。由於速效劑型的nifedipine被認為可迅速於腸道前段被吸收,因此我們推論CYP3A5*3/*3個體腸道前段可能有潛在的CYP3A4表現增加情形,而緩釋劑型主要應於腸道後段被吸收,故此區域CYP3A4表現增加情形可能相對較少。
英文摘要 CYP3A5 is polymorphically expressed in liver and small intestine. The nonfunctional CYP3A5*3 allele is primarily due to a SNP, g.6986A>G. People with at least one CYP3A5*1 allele express a higher amount of CYP3A5. Subjects without significant CYP3A5 expression were supposed to have higher plasma concentration and lower clearance. However, literature data are controversial when effects of CYP3A5 genotype on drug disposition were examined. Our previously report showed no difference in midazolam pharmacokinetics between CYP3A5*1/*3 and CYP3A5*3/*3 subjects, whereas significantly higher plasma concentrations of alprazolam, sirolimus, and tacrolimus in CYP3A5*3/*3 subjects were found in other studies. We postulated that there is a CYP3A4 up-regulation in the small intestine in CYP3A5*3/*3 subjects for some CYP3A5 substrates. To investigate the possible CYP3A4 up-regulation in different parts of the small intestine, we examined the effect of CYP3A5 genotype on nifedipine pharmacokinetics with different dosage forms in healthy male Chinese subjects. One group is given a single-dose of Adalat (immediate-release form of nifedipine), and the other group is given a single-dose of Coracten (extended-release form of nifedipine). Each group contains 12 CYP3A5*1/*3 subjects and 12 CYP3A5*3/*3 subjects. Blood samples were collected to analyze the pharmacokinetics of nifedipine. We found that CYP3A5 genotype has no effects on nifedipine pharmacokinetics in the Coracten study. However, in the Adalat study, CYP3A5*3/*3 subjects exhibited lower peak concentrations (71.5±54.5 ng/mL) than CYP3A5*1/*3 subjects (128.5±73.8 ng/mL) (P=0.04). The immediate-released nifedipine is supposed to be rapidly absorbed in the upper part of gastrointestinal tract. We therefore concluded a substantial up-regulation of CYP3A4 in the region, and the up-regulation is less in the lower gastrointestinal tract where the most of the extended-released nifedipine may be absorbed.
論文目次 中文摘要 ----------------------------------------------I
英文摘要 ----------------------------------------------III
誌謝 --------------------------------------------------IV
目錄 --------------------------------------------------V
圖目錄 ------------------------------------------------VI
表目錄 ------------------------------------------------VII
縮寫檢索表 --------------------------------------------VIII
第一章 緒論
一、Cytochrome P450 -----------------------------------1
二、CYP3A5基因多型性 ----------------------------------2
三、CYP3A5基因多型性對藥物代謝之影響 ------------------3
四、研究目的 ------------------------------------------4
第二章 實驗材料與儀器
一、實驗材料 ------------------------------------------7
二、實驗儀器 ------------------------------------------9
第三章 實驗方法
一、研究對象 ------------------------------------------10
二、CYP3A5基因型分析 ----------------------------------10
三、臨床試驗 ------------------------------------------13
四、以HPLC測量nifedipine血中濃度 ----------------------14
五、藥物動力學參數計算與統計分析 ----------------------15
第四章 實驗結果
一、鑑定CYP3A5、MDR1及CYP3A4基因型 --------------------16
二、人體試驗研究之HPLC與藥物動力學參數分析 ------------16
第五章 結論與討論
一、結論 ----------------------------------------------19
二、討論 ----------------------------------------------20
第六章 參考文獻 ---------------------------------------25
第七章 附錄
Adalat OROS® 受試者血中濃度 ---------------------------31
Adalat® 受試者血中濃度 --------------------------------35
Coracten® 受試者血中濃度 ------------------------------39
圖 ----------------------------------------------------43
表 ----------------------------------------------------52
自述 --------------------------------------------------62
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