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研究生:施貝姍
研究生(外文):Pei-Shan Shih
論文名稱:國人細胞色素3A5不同基因型對midazolam及其1’-hydroxy代謝物的藥動學研究
論文名稱(外文):Pharmacokinetics of midazolam and its 1’-hydroxy-metabolite in Chinese of different CYP3A5 genotypes
指導教授:黃金鼎黃金鼎引用關係
指導教授(外文):Jin-Ding Huang
學位類別:碩士
校院名稱:國立成功大學
系所名稱:藥理學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:中文
論文頁數:107
中文關鍵詞:細胞色素藥動學人體試驗國人
外文關鍵詞:human studyRFLPCYP3A5midazolam
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Cytochrome P450(細胞色素P450)是生物體內相關代謝的重要enzyme,而cytochrome P4503A (CYP3A) subfamily大量表現在人體主要代謝器官肝臟(25%)、腎臟、及胃腸道中,參與環境毒物、內生性物質、及大部分臨床用藥的代謝。
CYP3A subfamily的成員有:3A4、3A5、3A7,及3A43,成人肝臟主要表現3A4及3A5。CYP3A5佔肝臟CYP3A的 8%,而CYP 3A5的cDNA和CYP3A4有89.1%的相似性,amino acid和CYP3A4有84%的相似性,CYP3A5佔成人肝臟細胞色素 的7到8%。
CYP 3A5 的cDNA於1989年被分離出;2000年時發現在高加索人CYP 3A5P1的5-prime flanking region上有兩個相鄰的基因多型性現象:-369T/G及-44A/G (-44G allele出現比例為9.2%),並在以midazolam為probe的肝臟代謝CYP3A5 phenotype上有明顯的不同表現;2001年發現高加索人CYP 3A5P1 5-prime flanking region的基因多型性現象,伴隨著CYP 3A5*3 的基因多型性現象,形成不成熟的CYP3A5酵素,而影響肝臟CYP3A5代謝midazolam的phenotype。
本實驗室已知在中國人的CYP 3A5P1的5-prime flanking region上也有相同的相鄰的基因多型性現象存在,與高加索人相較之下,該-44G allele出現比例增加為28%;在此,我們收取42名志願受試者的血液,利用PCR及RFLP分析其CYP3A5基因型態,發現中國人CYP 3A5P1 5-prime flanking region的基因多型性現象亦伴隨著CYP 3A5 gene 的基因多型性現象(CYP 3A5*3)出現,39個人有CYP3A5*3基因型,一個人有CYP3A5*4或CYP3A5*5基因型,42人中並沒有發現CYP3A5*2或CYP3A5*6基因型。
進一步進行midazolam藥物動力學人體試驗研究,排除CYP 3A5其他基因型差異,選擇只有CYP 3A5*3不同基因型態的28名志願受試者,口服投予單一劑量7.5mg midazolam,收集受試者10個時間點的血液,以HPLC分析midazolam及其代謝物1'-hydroxymidazolam的血中濃度,研究不同基因型態肝臟CYP3A5代謝phenotype的影響。同型合子CYP3A5*3 (n= 14) 的受試者midazolam 0-8hr平均AUC值為9237 ± 1050 (mean±S.E.M.) ng-min/ml,異型合子CYP3A5*3/CYP3A5*1 (n=12)為7934 ± 768 ng-min/ml,而同型合子CYP3A5*3受試者 1'-hydroxymidazolam 0-8hr平均AUC值為3748 ± 427 ng-min/ml ,異型合子CYP3A5*3/CYP3A5*1為3920 ± 402 ng-min/ml。
結果顯示,中國人CYP3A5基因型為同型合子CYP3A5*3 或異型合子CYP3A5*3/CYP3A5*1,在midazolam和1'-hydroxymidazolam 藥物動力學是沒有明顯差異,即受試者的CYP3A5 酵素遺傳性多態現象對它的臨床意義或許並不大。
The CYP3A subfamily represents the most abundant cytochrome P450 in the human liver and gastrointestinal tract, and plays the most important role in xenobiotic metabolism. CYP3A5 is expressed for approximately 7 to 8 % of the total CYP content in human adult liver. The CYP3A5*3 variant is known to form premature CYP3A5. We recruited 42 Chinese volunteers to determine the genotypes of CYP3A5 by PCR-RFLP. Genotype analyses revealed that CYP3A5*3 allele existed in 39 of 42 volunteers, and CYP3A5*4 and CYP3A5*5 alleles were found in 1 of 42 volunteers; CYP3A5*2 and CYP3A5*6 alleles were not found. We excluded other genotypes of CYP3A5 to study the significance of CYP3A5*3 in midazolam pharmacokinetics. In the human study, each volunteer was gave a midazolam tablet (7.5 mg) orally. Series of blood samples were collected to analyze the time-course midazolam and 1’-hydroxymidazolam concentrations by HPLC. The average area under plasma concentration curve (AUC, 0-8 hr) of midazolam was 9237 ± 1050 (mean ± S.E.M.) ng-min/ml in homozygous CYP3A5*3 (n= 14) subjects, and 7934 ± 768 ng-min/ml in heterozygous CYP3A5*3/CYP3A5*1 (n= 12) subjects, and the average AUC (0-8 hr) of 1’-hydroxymidazolam was 3748 ± 427 ng-min/ml in homozygous CYP3A5*3 subjects, and 3920 ± 402 ng-min/ml in heterozygous CYP3A5*3/CYP3A5*1 subjects. The results show that midazolam and 1’-hydroxymidazolam pharmacokinetics is of no difference in subjects with or without CYP3A5 expression.
目 錄
中文摘要 1~2
英文摘要 3
第一章 緒論 4~12
第二章 實驗材料及方法
第一節 實驗材料 13~15
第二節 實驗儀器 16~17
第三節 實驗方法 18~30
第三章 實驗結果 31~34
第四章 討論 35~41
參考文獻 42~49
圖目錄 50~70
表目錄 71~78
附錄 79-107
自述
參考文獻

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