本文選題：異丙酚 + 靶控輸注��； 參考：《南京中醫(yī)藥大學》2014年碩士論文

【摘要】：背景 異丙酚是一種臨床常用的靜脈麻醉藥,目前主要采用靶控輸注的方式給藥。由于存在個體差異,臨床靶控輸注相同濃度的異丙酚時,個體患者藥效不同,表現(xiàn)為體內(nèi)異丙酚濃度的差異。我們需要采用個體化給藥的方式,對不同的患者采取不同的給藥方案。建立群體藥代動力學模型,用OFV值考察異丙酚代謝的影響因素,是實現(xiàn)個體化給藥一種有效的手段。 目的： 建立異丙酚在國人麻醉患者的PPK模型,為臨床個體化給藥提供參考。 方法： 1體內(nèi)實驗 1.1收集南京鼓樓醫(yī)院異丙酚麻醉手術(shù)病人22例,以1.0μg/mL為靶濃度,靶控輸注異丙酚,在6min、12min時分別采集血液樣本。采集完12min的樣本后將靶濃度設(shè)為2.0μg/mL,于TCI6min、12min分別采集血樣,采用高效液相-熒光檢測法對異丙酚的血藥濃度進行測定。采用執(zhí)行誤差(PE)中位數(shù)(MDPE)、PE絕對值中位數(shù)(MDAPE)、擺動度(wobble)、分散度(divergence)綜合評價TCI系統(tǒng)執(zhí)行情況。 1.2收集南京鼓樓醫(yī)院異丙酚麻醉手術(shù)病人44例,靶濃度設(shè)為2.5μg/mL于TCI2min、6mim、12min、60min、120min、180min及停止輸注異丙酚后2min、6min、30min、60min采集血樣。采用高效液相-熒光檢測法對異丙酚的血藥濃度進行測定。 2體外實驗 2.1建立異丙酚體外肝微粒體模型,研究異丙酚在肝微粒體中的酶促反應代謝動力學參數(shù),及不同抑制劑對異丙酚濃度的影響。 2.2采用聚合酶鏈反應和限制性核酸內(nèi)切酶方法分析患者的CYP2B6基因型頻率。 2.3采用非線性混合效應模型來建立異丙酚麻醉患者的最簡群體藥代動力學模型,OFV值評價基因多態(tài)性對血藥濃度的影響。 結(jié)果： 1體內(nèi)實驗 1.1高效液相色譜-熒光法測定的線性回歸方程：y=0.2911x+0.0211(r2=0.999),平均回收率大于90%,日內(nèi)與日間的RSD均小于8%。 1.2靶濃度為1.0μg/mL時MDPE在6分鐘和12分鐘分別為-53.5%,-47.0%,2.0μg/mL則分別為：-40.0%,-35.0%。1.0μg/mL時MDAPE在6分鐘和12分鐘分別為：53.5%,47.0%,2.0μg/mL則分別為40.0%,35.0%。1.0μg/mL時擺動度在6分鐘和12分鐘分別為53.0%,46.5%,2.0μg/mL則為39.6%,34.5%。1.0μg/mL時分散度在6分鐘和12分鐘分別為47.5%.h-1,35.0%.h-1,而2.0μg/mL則為34.0%.h-1,23.0%.h-1。 2體外實驗 2.1異丙酚的代謝動力米氏常數(shù)Vmax為172.413(μM·mg-1·min-1),最大反應速率Km為777.43(μM·L-1),清除率Clint為0.22(min-1·mg-1·protein)。在100～500μM濃度范圍內(nèi),CYP2B6的抑制劑氯吡格雷能夠顯著抑制異丙酚的代謝、而CYP2C9的抑制劑氟康唑和CYP2C19的抑制劑奧美拉唑則對異丙酚的代謝沒有顯著影響。 2.244例靶控輸注異丙酚麻醉患者中CYP2B6基因型為*1/*1為24例,*1/*6為18例,*6/*6為2例,基因頻率分別為53.3%,40.9%和4.5%。 2.3NONMEM軟件擬合出最簡群體藥代動力學模型,群體藥動學參數(shù)為：CL1、CL2、CL3分別為1.84、0.95、0.36mL·min-1·kg-1, V1、V2、V3分別為15.2、52.7、203L。 結(jié)論 1本實驗采用的高效液相色譜-熒光法測定靶控輸注異丙酚時體內(nèi)的藥物濃度,方法較為簡單,經(jīng)濟可靠。 2靶控輸注異丙酚,國人實測濃度與靶控濃度不同。我們需要建立國人的群體藥動學參數(shù),指導國人臨床異丙酚給藥。 3異丙酚在肝微粒體代謝反應過程中主要受代謝酶CYP2B6的作用。 4CYP2B6基因多態(tài)性可影響異丙酚在體內(nèi)的血藥濃度,臨床用藥時可以先測定患者基因型,對含有CYP2B6*6等位基因的患者用NONMEM軟件調(diào)整劑量。
[Abstract]:Background

Propofol is a commonly used intravenous anesthetics , which is mainly administered by target - controlled infusion . Due to individual differences , the efficacy of the individual patients is different , which is different from the concentration of propofol in the body due to the individual difference . We need to adopt the method of individualized administration , different dosage regimens can be taken for different patients . The influence factors of propofol metabolism are investigated by using the OFV value , which is an effective means to realize the individual administration .

Purpose :

The PPK model of propofol in patients with anesthesia was established to provide reference for clinical personalized administration .

Method :

in vivo experiment

The blood samples were collected at the concentration of 1.0 渭g / mL at 6 min and 12 min respectively . Blood samples were collected at 6 min and 12 min . Blood samples were collected at 6 min and 12 min .

1.2 The plasma concentration of propofol was determined by high performance liquid - fluorescence assay in 44 patients with propofol anesthesia operation in Nanjing Drum Tower . The target concentration was 2.5 渭g / mL in TCI2 min , 6 mim , 12 min , 60 min , 120 min , 180 min , and 2 min , 6 min , 30 min and 60 min after the infusion of propofol .

2 In vitro experiment

2.1 An in vitro rat liver microsomes model was established to study the enzymatic reaction kinetics parameters of propofol in liver microsomes and the effect of different inhibitors on propofol concentration .

2.2 The frequency of CYP2B6 genotype in patients was analyzed by polymerase chain reaction and restriction endonuclease analysis .

2.3 Using nonlinear mixed effect model to establish the most simple pharmacokinetic model of propofol anesthesia patients , the effect of gene polymorphism on plasma concentration was evaluated by OFV value .

Results :

in vivo experiment

1.1 The linear regression equation was determined by high performance liquid chromatography - fluorimetry : y = 0.2911x + 0.0211 ( r2 = 0.999 ) , the average recovery rate was more than 90 % , the RSD between day and day was less than 8 % .

When the concentration of MDPE was 1.0 渭g / mL , MDPE was - 53.5 % , - 47.0 % , 2.0 渭g / mL , respectively : - 40.0 % , - 37.0 % , 2.0 渭g / mL , respectively 41.0 % , 47.0 % , 2.0 渭g / mL , respectively 43.0 % , 47.0 % , 2.0 渭g / mL , respectively 47.0 % , 44.5 % , 2.0 渭g / mL , respectively 47.0 % , 44.5 % , 2.0 渭g / mL , respectively 47.0 % . h - 1 , 35.0 % . h - 1 , while 2.0 渭g / mL was 34.0 % . h - 1 , 23 . 0 % . h - 1 .

2 In vitro experiment

2.1 The metabolism of propofol was 172.413 ( 渭M 路 mg - 1 路 min - 1 ) , the maximum reaction rate Km was 777.43 ( 渭M 路 L - 1 ) , clearance Clint was 0.22 ( min - 1 路 mg - 1 路 protein ) . In the range of 100 - 500 渭M , the inhibitor of CYP2B6 inhibited the metabolism of propofol significantly , while inhibitor omeprazole and inhibitor omeprazole did not have a significant effect on the metabolism of propofol .

2.244 patients with target - controlled infusion of propofol were * 1 / * 1 in 24 cases , * 1 / * 6 for 18 cases , * 6 / * 6 for 2 cases , and gene frequencies of 54.3 % , 40.9 % and 4.5 % , respectively .

The pharmacokinetic parameters were 1 . 84 , 0 . 95 , 0.36 mL 路 min - 1 路 kg - 1 , V1 , V2 and V3 were 15.2 , 52.7 and 203L , respectively .

Conclusion

1 In this experiment , the drug concentration in the body was determined by high performance liquid chromatography - fluorimetry , which is simple and economical .

The measured concentration of propofol was different from the target control concentration . We need to establish the pharmacokinetic parameters of Chinese population to guide the Chinese clinical propofol administration .

The effect of 3 - propofol on the metabolism of liver microsomes was mainly influenced by CYP2B6 .

4CYP2B6 gene polymorphism can affect the concentration of propofol in the body , and the patient ' s genotype can be measured first , and the dose can be adjusted with NONMEM software in patients with CYP2B6 * 6 allele .
【學位授予單位】：南京中醫(yī)藥大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R969.1

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