本文關(guān)鍵詞：沙格雷酯藥物代謝動(dòng)力學(xué)研究　出處：《吉林大學(xué)》2017年碩士論文　論文類型：學(xué)位論文

  更多相關(guān)文章： 抗血栓 沙格雷酯 LC-MS/MS 藥代動(dòng)力學(xué) 生物等效性

【摘要】：研究目的沙格雷酯為抗血栓形成藥,主要用于改善慢性動(dòng)脈閉塞癥引起的潰瘍、疼痛以及冷感等缺血性癥狀,其出血并發(fā)癥少,在治療糖尿病病人血管病變上比阿司匹林更有效。沙格雷酯,化學(xué)名稱為(±)-2-(二甲胺基)-1-[[2-(3-甲氧基苯乙基)苯氧基]甲基]乙基丁二酸單酯,屬于酯類藥物,而酯類藥物易被血漿中的酯酶水解,并且由于自身結(jié)構(gòu)原因,沙格雷酯在見光的條件下不穩(wěn)定,因此測定血漿中沙格雷酯含量面臨著一定的挑戰(zhàn)。本論文在加入NaF(酯酶抑制劑)、避光保持沙格雷酯結(jié)構(gòu)穩(wěn)定的前提下,分別研究飲食與不同制劑對(duì)沙格雷酯在人體內(nèi)的藥代動(dòng)力學(xué)行為的影響,本研究采用了多重反應(yīng)監(jiān)控(MRM)的LC-MS/MS技術(shù),建立了適用于檢測人血漿中沙格雷酯的分析方法,將此方法用于測定人血漿中沙格雷酯的血藥濃度,計(jì)算沙格雷酯人體內(nèi)藥物代謝動(dòng)力學(xué)相關(guān)參數(shù),并對(duì)其藥物代謝動(dòng)力學(xué)參數(shù)進(jìn)行比較分析,為沙格雷酯在中國人體內(nèi)生物等效性的研究提供科學(xué)依據(jù)。研究方案建立了適用于檢測人血漿中沙格雷酯的LC-MS/MS分析方法。人體生物樣品經(jīng)有機(jī)試劑沉淀并利用固相萃取技術(shù)處理去除雜質(zhì)后,取20μl上清液,經(jīng)過Agela Technologies Venusil MP C18(4.6×100 mm,5μm)色譜柱,通過不同梯度的有機(jī)相和水相洗脫的方式進(jìn)行液相色譜分離,流動(dòng)相A為含0.02%甲酸的10 mM醋酸銨溶液,流動(dòng)相B為乙腈,LC-MS/MS系統(tǒng)用時(shí)為4.5 min。MS/MS系統(tǒng)采用ESI電噴霧離子源,正離子多重反應(yīng)離子掃描模式(MRM),用于定量的離子對(duì)分別為:沙格雷酯(430.3/135.1,m/z),內(nèi)標(biāo)地西泮(285.2/193.2,m/z)。本液相色譜-串聯(lián)質(zhì)譜的測定方法依照國家相關(guān)指導(dǎo)原則的要求,分別從特異性SPE、回歸線性、最低定量下限(LLOQ)、稀釋方法學(xué)(dilute)、準(zhǔn)確度、精密度、基質(zhì)效應(yīng)(ME)、提取回收率(RE)、殘留效應(yīng)(carry over)及所涉及的穩(wěn)定性等方面對(duì)本論文的LC-MS/MS方法進(jìn)行方法確證。利用所建立的LC-MS/MS定量分析方法測定人血漿中沙格雷酯的血藥濃度,并且繪制了沙格雷酯藥物濃度-時(shí)間曲線(即藥時(shí)曲線)。根據(jù)沙格雷酯的藥時(shí)曲線得出沙格雷酯藥物代謝動(dòng)力學(xué)的相關(guān)參數(shù)(藥時(shí)曲線下面積AUC0-∞、達(dá)峰時(shí)間Tmax、達(dá)峰濃度Cmax、消除半衰期t1/2等),并對(duì)以上藥代動(dòng)力學(xué)參數(shù)進(jìn)行分析,用于沙格雷酯藥代動(dòng)力學(xué)過程進(jìn)行相關(guān)評(píng)價(jià)。研究結(jié)果本論文建立了基于多重反應(yīng)監(jiān)測(MRM)模式檢測人血漿中沙格雷酯的液相色譜-串聯(lián)質(zhì)譜(LC-MS/MS)的分析方法,本方法有高度的靈敏度并且分析速度快,沙格雷酯和內(nèi)標(biāo)地西泮的批內(nèi)和批間的準(zhǔn)確度和精密度均達(dá)到了測試要求;經(jīng)過沉淀蛋白和固相萃取的兩部分樣品處理后,沙格雷酯和地西泮基本不受其他干擾性物質(zhì)的影響,同時(shí)具有較高的提取回收率;本方法能夠使待測物沙格雷酯的穩(wěn)定性在采血、運(yùn)輸、存儲(chǔ)和分析過程中得到保證。本方法符合CFDA指導(dǎo)原則的要求,滿足沙格雷酯藥代動(dòng)力學(xué)研究的要求,適用于沙格雷酯藥代動(dòng)力學(xué)及生物等效性的研究。
[Abstract]:The purpose of the study is sarpogrelate antithrombotic drugs, mainly used to improve chronic arterial occlusive disease caused by the ulcer, pain and cold ischemic symptoms, the fewer bleeding complications, more effective than aspirin in the treatment of diabetic vascular disease. Sarpogrelate, the chemical name is (+) -2- (two -1-[[2- (methylamino) 3- methoxy phenyl) phenoxy] methyl] ethyl succinate ester, belonging to drugs, and drug susceptible esterase hydrolysis esters in plasma, and because of their structure, Shug Ray did not see the light in the stable under the condition, so the determination of sarpogrelate hydrochloride in plasma facing certain challenges. In this paper, adding NaF (esterase inhibitor), light of sarpogrelate stable structure, respectively to study the effect of diet and different preparation of sarpogrelate hydrochloride in human body pharmacokinetics, this study adopts multiple reaction monitoring (MRM) of the LC-MS/MS technology, analysis method was established for detection of sarpogrelate in human plasma, the method for determination of plasma concentration in human plasma by Shug Ray, the calculation of sarpogrelate body pharmacokinetic parameters, and the pharmacokinetic parameters were compared and analyzed, as in China sarpogrelate in human bioequivalence study to provide scientific basis for. The research program was established for detection of sarpogrelate hydrochloride in human plasma by LC-MS/MS method. Human biological samples by organic reagents by solid phase extraction technique and precipitation treatment to remove impurities, take 20 l after Agela Technologies Venusil MP by C18 (4.6 * 100 mm, 5 m) column, through the organic and aqueous phases of different gradient elution methods of liquid chromatography separation, mobile phase containing A 0.02% formic acid 10 mM ammonium acetate solution, the B of mobile phase acetonitrile, LC-MS/MS system is 4.5 min. The MS/MS system adopts ESI electrospray ion source and positive ion multiplex reactive ion scanning mode (MRM). It is used for quantitative ion pair, namely Sagre ester (430.3/135.1, m/z), internal standard diazepam (285.2/193.2, m/z). The liquid chromatography tandem mass spectrometry method for the determination of the related guidelines in accordance with national requirements, from the specific SPE, linear regression, the lowest limit of quantification (LLOQ) and dilution methodology (dilute), accuracy, precision, matrix effect (ME) and the recovery rate (RE), residual effect (carry over) and the stability and other aspects of the LC-MS/MS method confirmed this method. Determination of serum concentration of sarpogrelate hydrochloride in human plasma by LC-MS/MS quantitative analysis method is established, and draw the sarpogrelate drug concentration time curve (i.e. the concentration time curve). According to the relevant parameters of sarpogrelate pharmacokinetic curve that the pharmacokinetics of the drug ester (area under the concentration time curve of AUC0- ~ Tmax, peak time, peak concentrations of Cmax, t1/2, and the elimination half-life) on the pharmacokinetic parameters were analyzed for evaluation of sarpogrelate pharmacokinetics. The research results of this thesis established a multiple reaction monitoring (MRM) mode based on the detection of human plasma sarpogrelate liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis method, this method has high sensitivity and fast analysis, Shug Ray and the internal standard of diazepam in batch and inter batch accuracy and precision were achieved the test requirements; after protein precipitation and solid phase extraction of two samples after treatment, sarpogrelate and diazepam are not affected by the interference of other substances, but also has high recovery rate; stability of this method can test Shug Ray to be guaranteed in the blood collection, transportation, storage and analysis process. This method meets the requirements of CFDA guidelines, meet the kinetics of sarpogrelate pharmacokinetics requirements, applicable to the study of sarpogrelate pharmacokinetics and bioequivalence.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R96

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