發(fā)布時間：2018-05-08 12:49

  本文選題：伊潘立酮 + 代謝產(chǎn)物P88��； 參考：《吉林大學(xué)》2014年碩士論文

【摘要】：研究目的 建立滿足伊潘立酮（ILP）臨床藥代動力學(xué)研究要求的同時定量分析人的血漿樣品中ILP及其代謝產(chǎn)物P88、P95的液相色譜-串聯(lián)質(zhì)譜（LC-MS/MS）方法；測定中國健康志愿者血漿樣品中ILP及其代謝產(chǎn)物P88、P95藥物濃度，繪制三種待測物的藥物濃度-時間曲線，分別計算其藥代動力學(xué)參數(shù)，考察其在體內(nèi)的藥代動力學(xué)特征，為伊潘立酮片上市提供數(shù)據(jù)支持。研究方法 使用以乙腈作為洗脫劑的固相萃取方法，對人血漿中的伊潘立酮及其代謝產(chǎn)物P88、P95進(jìn)行LC-MS/MS分析。以甲醇-10mM醋酸銨-0.1%甲酸溶液為流動相進(jìn)行梯度洗脫，三種待測物及內(nèi)標(biāo)苯海拉明經(jīng)SUPELCOAscentis-C18（50mm×4.6mm I.D.，5μm粒徑）分離后，進(jìn)入MS進(jìn)行檢測。選用電噴霧離子化源（ESI），采用正離子多重反應(yīng)監(jiān)測的模式（MRM），用于定量分析的離子對分別為：m/z427.3→m/z261.0（伊潘立酮），m/z429.3→m/z261.0（代謝產(chǎn)物P88），m/z429.3→m/z261.0（代謝產(chǎn)物P95）和m/z256.3→m/z167.1（內(nèi)標(biāo)苯海拉明）。根據(jù)美國食品藥品監(jiān)督管理局（FDA）的相關(guān)規(guī)定，本研究對該方法進(jìn)行了完整的確證，考察了該方法的精密度及準(zhǔn)確度、專屬性、線性范圍、最低定量下限、提取回收率、基質(zhì)效應(yīng)及各個條件下的穩(wěn)定性等。 本臨床試驗方案主要依照《赫爾辛基宣言》、《中華人民共和國藥品管理法》、等有關(guān)規(guī)定制定，選擇16名健康受試者口服1mg、3mg兩個劑量的伊潘立酮片后，經(jīng)不同時間采集血漿樣品并用LC-MS/MS方法測定血漿樣品中伊潘立酮及其代謝產(chǎn)物P88、P95的血藥濃度，繪制其藥物濃度-時間曲線，利用DAS3.0（Drugand statistics）軟件計算藥代動力學(xué)參數(shù)，并用SPSS進(jìn)行分析，研究伊潘立酮在人體內(nèi)的藥代動力學(xué)規(guī)律。研究結(jié)果 本研究建立的人血漿樣品中同時定量分析伊潘立酮及其代謝產(chǎn)物P88、P95的LC-MS/MS方法，在三種待測物和內(nèi)標(biāo)苯海拉明的出峰位置處均沒有發(fā)現(xiàn)內(nèi)源性干擾；伊潘立酮及其代謝產(chǎn)物P88、P95的線性范圍均為5-1500pg/mL，最低定量下限均為5pg/mL，低、中、高三個濃度QC樣品的準(zhǔn)確度、日內(nèi)及日間精密度均不超過±15%；伊潘立酮及其代謝產(chǎn)物P88、P95低、中、高三個濃度提取回收率分別為85.89±4.08%，95.17±6.93%，86.07±1.07%；97.98±5.29%，92.29±2.58%，84.04±0.34%和110.96±2.81%，97.00±7.68%，102.04±1.49%，提取回收率高并且穩(wěn)定；伊潘立酮及其代謝產(chǎn)物P88、P95的基質(zhì)效應(yīng)分別為81.96±5.10%，85.55±9.09%，95.86±1.97%；88.20±2.68%，91.18±10.05%，97.51±1.75%和91.27±5.04%，84.18±3.80%，98.39±2.02%，，基質(zhì)影響很��；血漿樣品在未經(jīng)提取處理和提取處理后的多種條件下穩(wěn)定性良好，相對誤差均不超過±15%；血漿樣品經(jīng)稀釋后10倍后再提取的準(zhǔn)確度和精密度均不超過±15%，血漿樣品的稀釋不影響樣品的測定。本課題所建立的人血漿樣品中同時定量分析伊潘立酮及其代謝產(chǎn)物P88、P95的LC-MS/MS方法，靈敏度高、選擇性好、分析時間短、重現(xiàn)性好且精密準(zhǔn)確，為伊潘立酮的臨床藥代動力學(xué)研究提供了支持。 16名中國健康受試者口服給予1mg和3mg伊潘立酮片，利用建立的LC-MS/MS方法檢測其血漿藥物濃度，繪制伊潘立酮及代謝產(chǎn)物P88和P95的藥物濃度-時間曲線，計算其藥代動力學(xué)參數(shù)。對伊潘立酮及代謝產(chǎn)物P88和P95的主要藥代動力學(xué)參數(shù)（AUC0-t、AUC0-∞和Cmax）進(jìn)行線性相關(guān)性分析。結(jié)果顯示，單次口服1~3mg劑量范圍內(nèi)的伊潘立酮片后，伊潘立酮在人體內(nèi)的藥代動力學(xué)過程符合非線性動力學(xué)過程。代謝產(chǎn)物P88和P95的藥代動力學(xué)過程是否符合線性藥動學(xué)過程暫無法判斷。
[Abstract]:research objective
To establish a quantitative analysis of ILP and its metabolites P88 and P95 by liquid chromatography tandem mass spectrometry (LC-MS/MS) in human plasma samples, which meet the clinical pharmacokinetic requirements of ILP (ILP), and determine the concentration of ILP and its metabolites P88, P95 drug concentration in the plasma samples of Chinese healthy volunteers, and draw the concentration of three kinds of drugs to be measured. The time curve was used to calculate its pharmacokinetic parameters, and to investigate its pharmacokinetic characteristics in vivo, so as to provide data support for the listing of ilpridone tablets.
Using acetonitrile as a eluant solid phase extraction method, the LC-MS/MS analysis of peridone and its metabolites P88, P95 in human plasma was carried out with the gradient elution of methanol -10mM acetate -0.1% formic acid solution as the mobile phase, and the separation of three kinds of samples and the internal standard SUPELCOAscentis-C18 (50mm x 4.6mm I.D., 5 micron m particle size) of the internal standard was separated. In MS, the electrospray ionization source (ESI) was selected and the mode of positive ion multiple reaction monitoring (MRM) was used. The ion pairs used for quantitative analysis were m/z427.3 to m/z261.0 (Pan Litong), m/z429.3 to m/z261.0 (metabolite P88), m/z429.3 to m/z261.0 (P95 of metabolites) and m/z256.3 to (internal standard phenhydramine). The relevant provisions of the food and Drug Administration (FDA) of the United States were confirmed in this study. The precision and accuracy of the method, specificity, linear range, minimum quantitative lower limit, extraction recovery, matrix effect and stability under various conditions were investigated.
The clinical trial scheme was formulated in accordance with the Helsinki declaration, the drug management law of People's Republic of China, and other relevant regulations. 16 healthy subjects were chosen to take oral 1mg, 3mg and two doses of peridone tablets. The plasma samples were collected at different time and LC-MS/MS method was used to determine the plasma samples and their metabolites P88, P95 The drug concentration time curve was plotted and the pharmacokinetic parameters were calculated by DAS3.0 (Drugand Statistics) software. The pharmacokinetics of peridone in human body was studied by SPSS analysis.
In the human plasma samples established in this study, the quantitative analysis of peridone and its metabolite P88, P95 LC-MS/MS method, no endogenous interference was found at the peak position of three kinds of subjects and internal standard diphenhydramine; the linear peri of irido Pan Litong and its metabolite P88, P95 were 5-1500pg/mL, and the lowest quantitative lower limit was 5pg/mL The accuracy of the QC samples of low, middle and high concentrations was not more than 15%. The recovery rates of the extraction of Pan Litong and its metabolites P88, P95, middle and high levels were 85.89 + 4.08%, 95.17 + 6.93%, 86.07 + 1.07%, 97.98 + 5.29%, 92.29 +, 92.29 +, 84.04 + 6.93%. The yield was high and stable, and the matrix effects of peridone and its metabolites P88, P95 were 81.96 + 5.10%, 85.55 + 9.09%, 95.86 + 1.97%, 88.20 + 2.68%, 91.18 + 10.05%, 97.51 + 1.75% and 91.27 + 5. The stability is good, the relative error is not more than 15%. The accuracy and precision of the plasma samples are not more than 15% after 10 times the dilution, and the dilution of the plasma samples does not affect the determination of the samples. The human plasma samples set up in this subject are simultaneously quantifying the LC-MS/MS method of the Irone and its metabolite P88, P95, and the spirit of the plasma sample. High sensitivity, good selectivity, short analysis time, good reproducibility and accuracy, which provide support for the clinical pharmacokinetics of irperidone.
16 Chinese healthy subjects were given 1mg and 3mg eperidone tablets. The concentration of plasma drugs was detected by the established LC-MS/MS method. The drug concentration time curves of eperidone and metabolic products P88 and P95 were plotted and the pharmacokinetic parameters were calculated. The main pharmacokinetic parameters of peridone and metabolic products P88 and P95 (AUC0-t, AUC0- infinity and Cmax) were used for linear correlation analysis. The results showed that the pharmacokinetic process of peridone in the human body was in line with the nonlinear kinetic process after a single dose of 1~3mg dose within a single dose of 1~3mg. The pharmacokinetic process of the metabolites P88 and P95 was not judged by the linear pharmacokinetics process.

【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R969.1

【參考文獻(xiàn)】

相關(guān)期刊論文 前4條

1 陳華;徐俊冕;;傳統(tǒng)和新型抗精神病藥物的選用[J];世界臨床藥物;2007年04期

2 薛靜;;第二次全國殘疾人抽樣調(diào)查最新數(shù)據(jù)公報[J];中國聽力語言康復(fù)科學(xué);2007年01期

3 鐘大放;以加權(quán)最小二乘法建立生物分析標(biāo)準(zhǔn)曲線的若干問題[J];藥物分析雜志;1996年05期

4 姜佐寧;治療精神障礙藥物:現(xiàn)代進(jìn)展與合理應(yīng)用[J];中國新藥雜志;1999年10期

本文編號：1861474