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癲癇患者左乙拉西坦群體藥動(dòng)學(xué)及MDR1 C3435T多態(tài)性研究

發(fā)布時(shí)間:2018-04-10 06:34

  本文選題:左乙拉西坦 切入點(diǎn):難治性癲癇 出處:《福建醫(yī)科大學(xué)》2014年碩士論文


【摘要】:目的 1.建立癲癇患者左乙拉西坦(LEV)群體藥動(dòng)學(xué)(PPK)模型,為個(gè)體化給藥提供參考。 2.探討MDR1C3435T多態(tài)性與癲癇耐藥的關(guān)系。 方法 1.建立高效液相色譜(HPLC)法測(cè)定LEV血藥濃度; 2.應(yīng)用聚合酶鏈反應(yīng)-限制性片段長(zhǎng)度多態(tài)性(PCR-RFLP)技術(shù)檢測(cè)MDR1C3435T; 3.應(yīng)用NONMEM法建立LEV群體藥動(dòng)學(xué)模型,考察患者生理指標(biāo)、LEV血藥濃度、MDR1C3435T基因型以及合并用藥等因素對(duì)LEV藥動(dòng)學(xué)參數(shù)的影響; 4.根據(jù)療效評(píng)級(jí)將癲癇患者分為耐藥組和敏感組,比較MDR1C3435T基因分型在兩組間的差異。 結(jié)果 1. HPLC法測(cè)定LEV血藥濃度,標(biāo)準(zhǔn)曲線(xiàn)回歸方程為y0.001x0.00173(r2=0.9994),線(xiàn)性范圍1~80μg mL-1。提取回收率86%~89%,,方法回收率99%~101%;日內(nèi)、日間精密度(RSD)<2%;最低檢測(cè)限0.5μg mL-1(S"N≥3)。 2.99例癲癇患者M(jìn)DR1C3435T基因型分布頻數(shù):CC型33例(33.3%)、CT型52例(52.6%)和TT型14例(14.1%);CC、CT和TT各基因型分布頻數(shù)的觀(guān)測(cè)值與理論值之間的差異無(wú)統(tǒng)計(jì)學(xué)意義(P=0.462,>0.05)。 3.基于99例癲癇患者150個(gè)血樣數(shù)據(jù)及相關(guān)指標(biāo),建立左乙拉西坦PPK模型,最終回歸模型為:0.303 清除率:CL2.45WT0.227(L-147e h),表觀(guān)分布容積: V27.7(L)。體重(WT)是影響左乙拉西坦藥動(dòng)學(xué)參數(shù)的主要因素。 4.耐藥組47例患者M(jìn)DR1C3435T基因型分布頻數(shù)分別為:CC型13例(27.66%)、CT型29例(61.7%)和TT型5例(10.64%);敏感組28例患者M(jìn)DR1C3435T基因分布頻數(shù)分別為CC型9例(32.14%)、CT型14例(50%)和TT型5例(17.86%);耐藥組患者C和T等位基因頻率分別為58.51%和41.49%,敏感組患者C和T等位基因頻率分別為57.14%和42.86%。CC、CT、TT基因型頻率和C、T等位基因頻率在兩組間的差異均無(wú)統(tǒng)計(jì)學(xué)意義(P值為0.082和0.774,>0.05)。 結(jié)論 1. HPLC法測(cè)定LEV血藥濃度簡(jiǎn)便易行,靈敏度高、準(zhǔn)確性好,適用于治療藥物監(jiān)測(cè)與藥動(dòng)學(xué)研究。 2. PCR-RFLP技術(shù)檢測(cè)MDR1C3435T,方法可行,結(jié)果可靠。 3.本文建立的癲癇患者左乙拉西坦PPK模型穩(wěn)定有效,具有較好預(yù)測(cè)能力,可為臨床制定個(gè)體化用藥提供參考。 4. MDR1C3435T多態(tài)性可能不是癲癇耐藥的影響因素。
[Abstract]:Purpose1.To establish a group pharmacokinetic model of levalacetam Lev in epileptic patients, and to provide reference for individualized administration.2.To investigate the relationship between MDR1C3435T polymorphism and drug resistance in epilepsy.Method1.A high performance liquid chromatography (HPLC) method was established to determine the concentration of LEV in blood.2.Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to detect MDR1C3435T;3.The pharmacokinetic model of LEV population was established by NONMEM method. The effects of the serum concentration of LEV and MDR1C3435T genotype and the combined use of drugs on the pharmacokinetic parameters of LEV were investigated.4.Patients with epilepsy were divided into drug resistant group and sensitive group according to the efficacy rating. The difference of MDR1C3435T genotyping between the two groups was compared.Result1.The serum concentration of LEV was determined by HPLC. The regression equation of standard curve was y0.001x0.00173r2O0.9994, and the linear range was 1U 80 渭 g mL -1.The recovery rate was 86% and 89% respectively. The recovery rate of the method was 99g / 101. During the day, the precision was less than 2. The lowest detection limit was 0. 5 渭 g mL-1(S "N 鈮

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