系統識別號 U0026-0812200915283825
論文名稱(中文) 轉送器P-glycoprotein的基因多型性對抗癲癇藥物phenytoin藥物動力學上的影響
論文名稱(英文) Effects of P-glycoprotein Polymorphism on Phenytoin Pharmacokinetics
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) 黃盈軒
研究生(英文) Ying-Syuan Huang
電子信箱 s2696403@mail.ncku.edu.tw
學號 s2696403
學位類別 碩士
語文別 中文
論文頁數 56頁
口試委員 口試委員-周辰熹
中文關鍵字 基因多型性  藥物動力學  抗癲癇藥物  P-醣蛋白 
英文關鍵字 AUC  bioavailability  phenytoin  polymorphism  Pgp 
中文摘要 P-醣蛋白(P-glycoprotein, Pgp)為一個具多重抗藥性的運送蛋白,在肝臟、小腸中將藥物運送出體外,在血腦屏障也可限制藥物進入腦部的含量,故Pgp的表現量及功能可能會影響其受質在血液中的濃度。許多文獻指出Pgp分別位於exon 21及exon 26的單核多型性(Single Nucleotide Polymorphism, SNP)2677G>T和3435C>T,與Pgp的表現量及活性有關,進而影響藥物在血液中的濃度。難治型癲癇 (Refractory epilepsy,RE) 病患產生抗藥性的現象目前推測可能是因為抗癲癇藥物在腦部堆積不足所引起,因此Pgp在RE病患腦部的表現量上升被認為與RE的形成有關。血腦屏障大量表現Pgp而運送抗癲癇藥物phenytoin至血液中可能是抗藥性產生的重要原因。另外文獻也指出Pgp在2677G>T和3435C>T的基因多型性與難治型癲癇有相關性,所以我們想要釐清除了在腦部大量表現的Pgp會影響phenytoin外,是否表現在腸道的Pgp也會因為Pgp的基因多型性而影響phenytoin在個體間的口服吸收率及其他藥動性質。
本計劃篩選Pgp基因型為G/G2677C/C3435 及T/T2677T/T3435之男性各十人,給予口服300 mg phenytoin,兩星期後靜脈注射210 mg phenytoin (假設phenytoin口服吸收率為70%,而靜脈注射時間與口服的Tmax時間相同,使兩階段達相同之濃度-時間曲線下面積(AUC)),再以HPLC分析血液中phenytoin的含量。基因型為T/T2677T/T3435受試者的平均口服吸收率為90.9%高於G/G2677C/C3435受試者82.1%,但無顯著差異;平均AUC(oral)、AUC(iv)及口服phenytoin後的 Cmax在兩基因型間並無差異;T1/2無論在口服或靜脈注射給藥下,在兩基因型間也無差異;而T/T2677T/T3435基因型的平均Tmax為10h則比G/G2677C/C3435基因型 6h來的高。由本試驗結果得知Pgp的基因多型性不會影響個體間對phenytoin的口服吸收率,而除了Tmax之外也不影響其他的藥物動力學性質。本試驗排除Pgp的基因多型性在吸收及排除層次上對phenytoin的影響;在難治型癲癇病患上可能因為Pgp在腦部的大量表現而影響phenytoin的藥效。本研究成果期能對個體間服用phenytoin的差異有進一的了解,進而希望具有臨床上之參考價值。
英文摘要 P-glycoprotein (Pgp) is a drug efflux pump in many organs, including the intestine and liver. Two SNPs of Pgp gene (2677G>T and 3435C>T) would affect function and expression of Pgp. Effects of Pgp polymorphism on drug disposition are controversial in the literature. It is difficult to predict pharmacokinetics from Pgp genotypes. Phenytoin is a substrate of Pgp. Persistent low phenytoin levels in plasma and Pgp overexpression in brain in several refractory epilepsy patients were reported. Pgp polymorphism may also affect efficacy by altering bioavailability of phenytoin. Our objective is to investigate how SNPs (2677G>T and 3435C>T) may affect absolute bioavailability of phenytoin. We selected two groups of 10 volunteers with haplotypes of G/G2677C/C3435 and T/T2677T/T3435 by PCR-RFLP. Each volunteer was orally given 300 mg of phenytoin and two weeks later intravenously infused with 210 mg of phenytoin at a rate for the same Tmax as the oral route (assume oral bioavailability is 70%). The design was to result a similar Cmax in oral and intravenous phases with consideration of non-linear metabolism of phenytoin. Series of blood samples were sampled for 72 hours. Concentrations of phenytoin in plasma are analyzed with HPLC. We found that the mean absolute bioavailability of phenytoin in T/T2677T/T3435 subjects (91%) is only slightly higher than in G/G2677C/C3435 subjects (82%). There were no difference in Cmax and AUC(oral) between two genotypic groups, however Tmax were higher in T/T2677T/T3435 subjects(10hr) than in G/G2677C/C3435 subjects(6hr). The study ruled out the possibility that genetic polymorphism of P-gp may affect phenytoin efficacy through a decreased absorption. Possible effect of P-gp SNPs on phenytoin efficacy in refractory epilepsy patients is probably due to effects in CNS.
論文目次 中文摘要 I
英文摘要 III
誌謝 Ⅳ
目錄 Ⅴ
表目錄 Ⅵ
圖目錄 Ⅶ
縮寫檢索表 Ⅷ
第一章 緒論 1
第二章 實驗材料與方法 10
第三章 實驗結果 17
第四章 討論 21
第五章 總結 27
參考文獻 28
附表 35
附圖 46
自述 56
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