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系統識別號 U0026-2907201016264900
論文名稱(中文) CYP3A5基因型對不同劑型的鈣離子阻斷劑nifedipine在女性藥物動力學上的影響
論文名稱(英文) Effects of CYP3A5 genotype on female 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 98
學期 2
出版年 99
研究生(中文) 林雅文
研究生(英文) Ya-Wen Lin
學號 s2697411
學位類別 碩士
語文別 中文
論文頁數 100頁
口試委員 指導教授-黃金鼎
共同指導教授-賴明亮
口試委員-周辰熹
中文關鍵字 CYP3A4  CYP3A5  基因多型性  Nifedipine  劑型  女性  藥物動力學 
英文關鍵字 CYP3A4  CYP3A5  Polymorphism  Nifedipine  Dosage form  Female  Pharmacokinetics 
學科別分類
中文摘要 Cytochrome P450類代謝酵素對體內及外來物質的代謝作用扮演相當重要的角色,其中以CYP3A4為最主要代謝酵素,但CYP3A5亦有相當程度的貢獻,且經CYP3A5代謝的受質與CYP3A4有非常高的重複性。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的6986A>G最被廣泛研究,帶有此SNP的allele命名為CYP3A5*3,會造成mRNA錯誤的切割,並轉譯出沒有功能的蛋白質,因此個體若為CYP3A5*3/*3同型合子則缺乏CYP3A5的表現。
理論上缺乏CYP3A5表現 (CYP3A5-negative) 的個體代謝CYP3A5受質的能力較差,受質血中濃度應較高,但綜合過去許多研究結果卻非常分歧。本實驗室先前研究帶有不同CYP3A5基因型的男性個體對不同劑型的nifedipine藥物動力學之影響,結果顯示速效劑型的Adalat在CYP3A5*1/*3 (positve) 的男性個體血中濃度明顯高於CYP3A5*3/*3 (negative) 的男性個體;而緩釋劑型Coracten的藥物動力學則不受CYP3A5基因型所影響。推論由於速效劑型的Adalat主要是在腸道前段被吸收,暗示CYP3A5*3/*3 (negative) 的男性個體在腸道前段可能有潛在CYP3A4 代償性表現增加的情形;而緩釋劑型的Coracten則推測應在腸道後段被吸收,所以認為CYP3A5*3/*3 (negative) 的男性個體在腸道後段CYP3A4的代償性表現增加情形就相對較少。
已知女性本身的CYP3A4表現量較男性來的高,為了進一步確認在女性腸道的不同部位,不同CYP3A5基因型CYP3A4代償性表現增加的差異性,我們同樣以nifedipine兩種不同劑型的藥物來進行人體試驗,各組含有12位CYP3A5*1/*3及12位CYP3A5*3/*3的健康女性受試者,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Adalat的試驗中,CYP3A5基因型並不影響女性nifedipine的藥物動力學。然而,在Coracten的試驗中,CYP3A5*1/*3 (positve) 的女性受試者相較於CYP3A5*3/*3 (negative) 有較高的最大血中濃度 (分別為55.5±12.5 ng/mL及44.1±12.2 ng/mL,P=0.033),暗示CYP3A5*3/*3 (negative) 的女性個體在腸道後段可能有潛在CYP3A4 代償性表現增加的情形,在腸道的前段則是CYP3A4代償性表現增加的情形相對較少,與男性試驗的部份呈現相反的結果。因此綜合上述結果,CYP3A5的基因多型性對於其受質藥物動力學的影響是存在性別以及腸道部位的差異性的,顯示在藥物治療的過程中,對於性別不同帶有不同CYP3A5基因型的個體,不同藥物劑型的選擇以及劑量的調整也可能是一項考慮因素。
英文摘要 CYP3A5 is polymorphically expressed in liver and small intestine primarily due to a SNP (6986A>G) in intron 3 of the CYP3A5 gene (known as the CYP3A5*3 allele), which causes mRNA misplicing. People with at least one CYP3A5*1 allele express large amounts of CYP3A5. Subjects without CYP3A5 expression was supposed to have a higher plasma concentration and lower clearance of drugs. However, literature data are controversial when effects of CYP3A5 genotype on drug disposition were examined. Our laboratory previously reported that in the Adalat study, CYP3A5*1/*3 (positve) male subjects exhibited a higher nifedipine plasma concentration than CYP3A5*3/*3 (negative) male subjects, whereas the CYP3A5 genotype has no effect on male nidedipine pharmacokinetics in the Coracten study. We postulated that the immediate-release form of nifedipine (Adalat) is supposed to be rapidly absorbed in the duodenum or jejunum, while the slow-release form of nifedipine (Coracten) is possibly absorbed in the ileum. The results implicated that there is a significant CYP3A4 up-regulation in the upper part of small intestine in male CYP3A5*3/*3 subjects. We know that female have higher CYP3A4 expression than male. To confirm the possible CYP3A4 up-regulation in different parts of small intestine on female, we recruited healthy female volunteers. One group given a single dose of Adalat and the other given a single dose of Coracten. Each group contains 12 CYP3A5*1/*3 and 12 CYP3A5*3/*3 female subjects. Blood samples were collected to analyze the pharmacokinetics of nifedipine. In contrast to male results, we found that CYP3A5 genotype has no effect on female nidedipine pharmacokinetics in the Adalat study, whereas in the Coracten study, CYP3A5*1/*3 (positive) female subjects exhibited a higher peak concentration (55.5±12.5 ng/mL) than CYP3A5*3/*3 (negative) female subjects (44.1±12.2 ng/mL) (P=0.033). The results implicated that there is a significant CYP3A4 up-regulation in the lower part of small intestine in female CYP3A5*3/*3 subjects. The contrary results between male and female suggest a gender difference and a dosage-form dependent pharmacotherapy.
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基因多型性對其受質藥物代謝之影響 ---------------- 4
四、本實驗室探討不同CYP3A5基因型對其受質藥物代謝之影響 ------- 4
五、研究目的 ------------------------------------------ 7
六、試驗用藥Adalat、Coracten 之藥品特性 ----------------- 9
第二章 實驗材料
一、實驗儀器 ----------------------------------------- 10
二、實驗材料 ----------------------------------------- 11
第三章 實驗方法
ㄧ、CYP3A5基因型分析 --------------------------------- 14
二、臨床試驗 ----------------------------------------- 21
三、以HPLC分析血液中nifedipine濃度 --------------------- 23
四、藥物動力學參數計算與數據統計分析 ---------------------- 26
第四章 實驗結果
ㄧ、CYP3A5、MDR1及CYP3A4基因型鑑定 -------------------- 27
二、HPLC確效 ----------------------------------------- 28
三、CYP3A5基因型對不同劑型的nifedipine在女性藥動上之影響 --- 29
四、CYP3A5基因型對其受質藥物的藥動影響之男女性別差異 -------- 31
第五章 結論與討論
一、結論 --------------------------------------------- 33
二、討論 --------------------------------------------- 34
第六章 參考文獻 ------------------------------------------ 44
第七章 附錄
ㄧ、Adalat® 受試者血中濃度及藥動參數 --------------------- 56
二、Coracten® 受試者血中濃度及藥動參數-------------------- 64
圖 ----------------------------------------------------- 72
表 ----------------------------------------------------- 88
自述 --------------------------------------------------- 100
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