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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
指導教授-黃金鼎
指導教授-賴明亮
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 
學科別分類
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
參考文獻 Ambudkar SV, Dey S, Hrycyna CA, Ramachandra M, Pastan I, Gottesman MM. (1999) Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annu Rev Pharmacol Toxicol 39: 361-98

Baltes S, Gastens AM, Fedrowitz M, Potschka H, Kaever V, Lscher W. (2007) Differences in the transport of the antiepileptic drugs phenytoin, levetiracetam and carbamazepine by human and mouse P-glycoprotein. Neuropharmacology 52: 333-46

Chen CJ, Chin JE, Ueda K, Clark DP, Pastan I, Gottesman MM, Roninson IB. (1986) Internal duplication and homology with bacterial transport proteins in the mdr1 (P-glycoprotein) gene from multidrug-resistant human cells. Cell 47: 381-9

Dean M, Hamon Y, Chimini G. (2001) The human ATP-binding cassette (ABC) transporter superfamily. J Lipid Res 42: 1007-17

Dietrich CG, Geier A, Oude Elferink RP. (2003) ABC of oral bioavailability: transporters as gatekeepers in the gut. Gut 52: 1788-95

Fromm MF. (2000) P-glycoprotein: a defense mechanism limiting oral bioavailability and CNS accumulation of drugs. Int J Clin Pharmacol Ther 38: 69-74

Gerloff T, Schaefer M, Johne A, Oselin K, Meisel C, Cascorbi I, Roots I. (2002) MDR1 genotypes do not influence the absorption of a single oral dose of 1 mg digoxin in healthy white males. Br J Clin Pharmacol 54: 610-6

Higgins CF, Gottesman MM. (1992) Is the multidrug transporter a flippase? Trends Biochem Sci 17: 18-21

Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmller J, Johne A,Cascorbi I, Gerloff T, Roots I, Eichelbaum M, Brinkmann U. (2000) Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci U S A 97: 3473-8

Horinouchi M, Sakaeda T, Nakamura T, Morita Y, Tamura T, Aoyama N, Kasuga M, Okumura K. (2002) Significant genetic linkage of MDR1 polymorphisms at positions 3435 and 2677: functional relevance to pharmacokinetics of digoxin. Pharm Res 19: 1581-5

Goto M, Masuda S, Saito H, Uemoto S, Kiuchi T, Tanaka K, Inui K. (2002) C3435T polymorphism in the MDR1 gene affects the enterocyte expression level of CYP3A4rather than Pgp in recipients of living-donor liver transplantation. Pharmacogenetics 12: 451-7

Hung CC, Tai JJ, Lin CJ, Lee MJ, Liou HH. (2005) Complex haplotypic effects of the ABCB1 gene on epilepsy treatment response. Pharmacogenomic. 6: 411-7

Hung CC, Chen CC, Lin CJ, Liou HH. (2008) Functional evaluation of polymorphisms in the human ABCB1 gene and the impact on clinical responses of antiepileptic drugs. Pharmacogenet Genomics 18: 390-402

Johne A, Kpke K, Gerloff T, Mai I, Rietbrock S, Meisel C, Hoffmeyer S, Kerb R, Fromm MF, Brinkmann U, Eichelbaum M, Brockmller J, Cascorbi I, Roots I. (2002) Modulation of steady-state kinetics of digoxin by haplotypes of the P-glycoprotein MDR1 gene. Clin Pharmacol Ther 72: 584-94

Loscher W, Potschka H. (2002) Role of multidrug transporters in pharmacoresistance to antiepileptic drugs. J Pharmacol Exp Ther
301: 7-14

Juliano RL, Ling V. (1976) A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta 455: 152-62

Juranka PF, Zastawny RL, Ling V. (1989) P-glycoprotein: multidrug- resistance and a superfamily of membrane-associated transport proteins. FASEB J 3: 2583-92.

Kerb R, Hoffmeyer S, Brinkmann U. (2001(a)) ABC drug transporters: hereditary polymorphisms and pharmacological impact in MDR1, MRP1 and MRP2. Pharmacogenomics 2: 51-64

Kerb R, Aynacioglu AS, Brockmoller JSchlagenhaufer R, Bauer S, Szekeres T, Hamwi A, Fritzer-Szekeres M, Baumgartner C, Ongen HZ, Guzelbey P, Roots I, Brinkmann U. (2001) The predictive value of MDR1, CYP2C9, and CYP2C19 polymorphisms for phenytoin plasma levels. The Pharmacogenomics Journal 1: 204-10

Kim RB, Leake BF, Choo EF, Dresser GK, Kubba SV, Schwarz UI, Taylor A, Xie HG, McKinsey J, Zhou S, Lan LB, Schuetz JD, Schuetz EG, Wilkinson GR. (2001) Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther 70: 189-99

Kurata Y, Ieiri I, Kimura M, Morita T, Irie S, Urae A, Ohdo S, Ohtani H,Sawada Y, Higuchi S, Otsubo K. (2002) Role of human MDR1 gene polymorphism in bioavailability and interaction of digoxin, a substrate of P-glycoprotein. Clin Pharmacol Ther 72: 209-19

Kwan P, Brodie MJ. (2005) Potential role of drug transporters in the pathogenesis of medically intractable epilepsy. Epilepsia 46: 224-35

Loscher W, Potschka H. (2002) Role of multidrug transporters in pharmacoresistance to antiepileptic drugs. J Pharmacol Exp Ther 301: 7-14

Lazarowski A, Sevlever G, Taratuto A, Massaro M, Rabinowicz A. (1999) Tuberous sclerosis associated with MDR1 gene expression and drug-resistant epilepsy. Pediatr Neurol 21: 731-4

Nakamura T, Sakaeda T, Horinouchi M, Tamura T, Aoyama N, Shirakawa T, Matsuo M, Kasuga M, Okumura K. (2002) Effect of the mutation (C3435T) at exon 26 of the MDR1 gene on expression level of MDR1 messenger ribonucleic acid in duodenal enterocytes of healthy Japanese subjects. Clin Pharmacol Ther 71: 297-303

Potschka H, Lscher W. (2001) In vivo evidence for P-glycoprotein- mediated transport of phenytoin at the blood-brain barrier of rats. Epilepsia 42: 1231-40

Regesta G, Tanganelli P. (1999) Clinical aspects and biological bases of
drug-resistant epilepsies. Epilepsy Res 34: 109-22

Rivers F, O'Brien TJ, Callaghan R. (2008) Exploring the possible interaction between anti-epilepsy drugs and multidrug efflux pumps; in vitro observations. Eur J Pharmacol 598: 1-8

Rizzi M, Caccia S, Guiso G, Richichi C, Gorter JA, Aronica E, Aliprandi M, Bagnati R, Fanelli R, D'Incalci M, Samanin R, Vezzani A. (2002) Limbic seizures induce P-glycoprotein in rodent brain: functional implications for pharmacoresistance. J Neurosci 22: 5833-9

Sakaeda T, Nakamura T, Horinouchi M, Kakumoto M, Ohmoto N, Sakai T, Morita Y, Tamura T, Aoyama N, Hirai M, Kasuga M, Okumura K. (2001) MDR1 genotype-related pharmacokinetics of digoxin after single oral administration in healthy Japanese subjects. Pharm Res 18: 1400-4
Sander JW. (1993) Some aspects of prognosis in the epilepsies-a review. Epilepsia 34: 1007-16

Schinkel AH, Wagenaar E, Mol CA, van Deemter L. (1996) P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J Clin Invest 97: 2517-24

Schinkel AH. (1999) P-Glycoprotein, a gatekeeper in the blood-brain barrier. Adv Drug Deliv Rev 36: 179-194

Siddiqui A, Kerb R, Weale ME, Brinkmann U, Smith A, Goldstein DB, Wood NW, Sisodiya SM. (2003) Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCB1. N Engl J Med 348: 1480-2

Siegmund W, Ludwig K, Giessmann T, Dazert P, Schroeder E, Sperker B, Warzok R, Kroemer HK, Cascorbi I. (2002) The effects of the human MDR1 genotype on the expression of duodenal P-glycoprotein and disposition of the probe drug talinolol. Clin Pharmacol Ther 72: 572-83

Sisodiya SM, Heffernan J, Squier MV. (1999) Over-expression of P-glycoprotein in malformations of cortical development. Neuroreport 10: 3437-41

Sisodiya SM, Lin WR, Harding BN, Squier MV, Thom M. (2002) Drug
resistance in epilepsy: expression of drug resistance proteins in common causes of refractory epilepsy. Brain 125: 22-31

Tanabe M, Ieiri I, Nagata N, Inoue K, Ito S, Kanamori Y, Takahashi M, KurataY, Kigawa J, Higuchi S, Terakawa N, Otsubo K. (2001) Expression of P-glycoprotein in human placenta: relation to genetic polymorphism of the multidrug resistance (MDR)-1 gene. J Pharmacol Exp Ther 297: 1137-43
Tanigawara Y. (2000) Role of P-glycoprotein in drug disposition. Ther Drug Monit 22: 137-40

Terao T, Hisanaga E, Sai Y, Tamai I, Tsuji A.( 1996) Active secretion of drugs from the small intestinal epithelium in rats by P-glycoprotein functioning as an absorption barrier. J Pharm Pharmacol 48: 1083-9

Tishler DM, Weinberg KI, Hinton DR, Barbaro N, Annett GM, Raffel C. (1995) MDR1 gene expression in brain of patients with medically intractable epilepsy. Epilepsia 36: 1-6

Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC. (1987) Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci U S A 84: 7735-8

Tsai JJ, Lai ML, Kao Yang YH, Huang JD. (1992) Comparison on bioequivalence of four phenytoin preparations in patients with multiple-dose treatment. J Clin Pharmacol 32: 272-6

Turgut G, Kurt E, Sengul C, Alatas G, Kursunluoglu R, Oral T, Turgut S, Herken H. (2007) Association of MDR1 C3435T polymorphism with bipolar disorder in patients treated with valproic acid. Mol Biol Rep 36: 495-9

Ueda K, Clark DP, Chen CJ, Roninson IB, Gottesman MM, Pastan I. (1987) The human multidrug resistance (mdr1) gene. cDNA cloning and transcription initiation. J Biol Chem 262: 505-8

van der Holt B, Van den Heuvel-Eibrink MM, Van Schaik RH, van der Heiden IP, Wiemer EA, Vossebeld PJ, Lwenberg B, Sonneveld P. (2006) ABCB1 gene polymorphisms are not associated with treatment outcome in elderly acute myeloid leukemia patients. Clin Pharmacol Ther 80: 427-39
Verstuyft C, Schwab M, Schaeffeler E, Kerb R, Brinkmann U, Jaillon P, Funck-Brentano C, Becquemont L. (2003) Digoxin pharmacokinetics and MDR1 genetic polymorphisms. Eur J Clin Pharmacol 58: 809-12

von Richter O, Burk O, Fromm MF, Thon KP, Eichelbaum M, Kivist KT. (2004) Cytochrome P450 3A4 and P-glycoprotein expression in human small intestinal enterocytes and hepatocytes: a comparative analysis in paired tissue specimens. Clin Pharmacol Ther 75: 172-83

Weiss J, Kerpen CJ, Lindenmaier H, Dormann SM, Haefeli WE. (2003) Interaction of antiepileptic drugs with human P-glycoprotein in vitro. J Pharmacol Exp Ther 307: 262-7

Zhang Y, Benet LZ. (2001) The gut as a barrier to drug absorption: combined role of cytochrome P450 3A and P-glycoprotein. Clin Pharmacokinet 40: 159-68
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