异丙酚群体药代动力学及其代谢酶基因多态性研究

发布时间：2018-06-24 01:00

本文选题：异丙酚 + 靶控输注　；参考：《南京中医药大学》2014年硕士论文

【摘要】：背景异丙酚是一种临床常用的静脉麻醉药,目前主要采用靶控输注的方式给药。由于存在个体差异,临床靶控输注相同浓度的异丙酚时,个体患者药效不同,表现为体内异丙酚浓度的差异。我们需要采用个体化给药的方式,对不同的患者采取不同的给药方案。建立群体药代动力学模型,用OFV值考察异丙酚代谢的影响因素,是实现个体化给药一种有效的手段。目的：建立异丙酚在国人麻醉患者的PPK模型,为临床个体化给药提供参考。方法： 1体内实验 1.1收集南京鼓楼医院异丙酚麻醉手术病人22例,以1.0μg/mL为靶浓度,靶控输注异丙酚,在6min、12min时分别采集血液样本。采集完12min的样本后将靶浓度设为2.0μg/mL,于TCI6min、12min分别采集血样,采用高效液相-荧光检测法对异丙酚的血药浓度进行测定。采用执行误差(PE)中位数(MDPE)、PE绝对值中位数(MDAPE)、摆动度(wobble)、分散度(divergence)综合评价TCI系统执行情况。 1.2收集南京鼓楼医院异丙酚麻醉手术病人44例,靶浓度设为2.5μg/mL于TCI2min、6mim、12min、60min、120min、180min及停止输注异丙酚后2min、6min、30min、60min采集血样。采用高效液相-荧光检测法对异丙酚的血药浓度进行测定。 2体外实验 2.1建立异丙酚体外肝微粒体模型,研究异丙酚在肝微粒体中的酶促反应代谢动力学参数,及不同抑制剂对异丙酚浓度的影响。 2.2采用聚合酶链反应和限制性核酸内切酶方法分析患者的CYP2B6基因型频率。 2.3采用非线性混合效应模型来建立异丙酚麻醉患者的最简群体药代动力学模型,OFV值评价基因多态性对血药浓度的影响。结果： 1体内实验 1.1高效液相色谱-荧光法测定的线性回归方程：y=0.2911x+0.0211(r2=0.999),平均回收率大于90%,日内与日间的RSD均小于8%。 1.2靶浓度为1.0μg/mL时MDPE在6分钟和12分钟分别为-53.5%,-47.0%,2.0μg/mL则分别为：-40.0%,-35.0%。1.0μg/mL时MDAPE在6分钟和12分钟分别为：53.5%,47.0%,2.0μg/mL则分别为40.0%,35.0%。1.0μg/mL时摆动度在6分钟和12分钟分别为53.0%,46.5%,2.0μg/mL则为39.6%,34.5%。1.0μg/mL时分散度在6分钟和12分钟分别为47.5%.h-1,35.0%.h-1,而2.0μg/mL则为34.0%.h-1,23.0%.h-1。 2体外实验 2.1异丙酚的代谢动力米氏常数Vmax为172.413(μM·mg-1·min-1),最大反应速率Km为777.43(μM·L-1),清除率Clint为0.22(min-1·mg-1·protein)。在100～500μM浓度范围内,CYP2B6的抑制剂氯吡格雷能够显著抑制异丙酚的代谢、而CYP2C9的抑制剂氟康唑和CYP2C19的抑制剂奥美拉唑则对异丙酚的代谢没有显著影响。 2.244例靶控输注异丙酚麻醉患者中CYP2B6基因型为*1/*1为24例,*1/*6为18例,*6/*6为2例,基因频率分别为53.3%,40.9%和4.5%。 2.3NONMEM软件拟合出最简群体药代动力学模型,群体药动学参数为：CL1、CL2、CL3分别为1.84、0.95、0.36mL·min-1·kg-1, V1、V2、V3分别为15.2、52.7、203L。结论 1本实验采用的高效液相色谱-荧光法测定靶控输注异丙酚时体内的药物浓度,方法较为简单,经济可靠。 2靶控输注异丙酚,国人实测浓度与靶控浓度不同。我们需要建立国人的群体药动学参数,指导国人临床异丙酚给药。 3异丙酚在肝微粒体代谢反应过程中主要受代谢酶CYP2B6的作用。 4CYP2B6基因多态性可影响异丙酚在体内的血药浓度,临床用药时可以先测定患者基因型,对含有CYP2B6*6等位基因的患者用NONMEM软件调整剂量。
[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 .
【学位授予单位】：南京中医药大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R969.1

【参考文献】