丙泊酚靶控输注时效应室平衡速率常数选择的药物代谢动力学模型特异性  

Pharmacokinetic model-specific effect-site equilibrium rate constant of propofol during target-controlled infusion

作　　者：龚航 张顺吉 李涛 杨雪辉 张宇 李鲜 李建钢 GONG Hang;ZHANG Shunji;LI Tao;YANG Xuehui;ZHANG Yu;LI Xian;LI Jian gang(Department of Anesthesiology,the First People s Hospital of Qujing City,Qujing 655000,China;Department of Stomatology,the First People s Hospital of Qujing City,Qujing 655000,China;Faculty of Pharmacy,Kunming Medical University,Kunming 650500,China)

机构地区：[1]曲靖市第一人民医院麻醉科,曲靖655000 [2]曲靖市第一人民医院口腔科,曲靖655000 [3]昆明医科大学药学院,昆明650500

出　　处：《西北药学杂志》2022年第1期125-130,共6页Northwest Pharmaceutical Journal

基　　金：国家自然科学基金项目(编号:31860087)。

摘　　要：目的研究丙泊酚靶控输注(TCI)时效应室平衡速率常数(Ke0)取值的药物代谢动力学(PK)模型特异性以及潜在的人群特异性。方法64例择期全身麻醉手术患者随机接受TCI系统Schnider模型和Marsh模型,并且设置血浆质量浓度为4.2μg·mL^(-1),持续输注15 min;输注过程中丙泊酚的效应室质量浓度首先采用系统自带Ke0值预测。TCI开始后以10 s间隔同步下载脑电双频指数(BIS)值和TCI输注原始数据,同时每10 s测试患者睫毛反射并记录睫毛反射消失时间。采用S型效应室质量浓度-效应关系描述药效学,基于非线性混合效应模型拟合药效学参数并推定模型特异性Ke0值。目标函数(Objective function)减少大于6.63(卡方分布,自由度=1)等效于模型显著改善(P<0.01)。结果不同PK模型TCI的患者年龄、性别、身高、体质量与体质量指数(BMI)相似。睫毛反射消失时,Marsh模型TCI患者相比Schnider模型TCI患者时间较短、丙泊酚用量较大(P<0.05);虽然前者BIS值较高但系统自带Ke0预测的效应室质量浓度却较低。考虑模型特异性时,药效学模型拟合的目标函数值从14448.721降低到14412.619(P<0.01)。最终的药效学模型参数特征值为:无丙泊酚作用时BIS基础值(E_(0))=94.9,最大效应值(E_(max))=7.93,产生50%最大效应时的效应室质量浓度(CE_(50))=3.68μg·mL^(-1),曲线斜率(γ)=1.74;Marsh模型和Schnider模型特异性Ke0值分别为0.492、0.131 min^(-1)。此外,经模型拟合后,上述药效学矛盾现象消失。结论TCI药物输注时,Ke0取值具有PK模型特异性和人群特异性,不加选择随意选择Ke0值会导致效应室质量浓度拟合错误并导致靶控效应室质量浓度输注不正确。Objective To determine whether the value of effect-site equilibrium rate constant(Ke0)of propofol is specific to the pharmacokinetic(PK)model and population during target-controlled infusion(TCI).Methods 64 patients undergoing elective general anesthesia randomly received TCI with plasma concentration 4.2μg·mL^(-1) according to Schnider model or Marsh model for 15 minutes.The effect-site concentration of propofol was predicted firstly with the system-provided Ke0 value during the infusion.The BIS value and the original TCI infusion data were downloaded simultaneously at 10 seconds intervals.At the same time,the disappearance of eyelash reflex of the patient was tested and recorded.Sigmoid effect-site concentration-effect relationship was used to describe pharmacodynamics.The pharmacodynamic parameters were fitted based on a nonlinear mixed-effect model and the PK model-specific Ke0 value was estimated.A reduction in the objective function greater than 6.63(Chi-squared distribution,df=1)was equivalent to a significant improvement in the model fitting(P<0.01).Results The age,gender,height,weight and body mass index of patients with TCI of the different PK models were similar.When the eyelash reflex disappeared,the patients with Marsh model TCI had shorter time and larger propofol dosage than those with Schnider model TCI and the corresponding effect-site concentration was lower(P<0.05).Paradoxically,the former had a higher BIS value,but the effect-site concentration predicted by the system-provided Ke0 value was lower.When considering the specificity of the model,the objective function of pharmacodynamics decreased from 14448.721 to 14412.619(P<0.01).The typical values of the final pharmacodynamic model parameters were as follows:E_(0)=94.9,E_(max)=7.93,CE_(50)=3.68μg·mL^(-1),γ=1.74;the specific Ke0 values for Marsh and Schnider model were 0.492 min^(-1) and 0.131 min^(-1) respectively;in addition,the above-mentioned paradoxical pharmacodynamics disappeared.Conclusion The Ke0 value has PK model specificity and

关 键 词：丙泊酚 药效学 效应室平衡速率常数(Ke0) 药物代谢动力学 

分 类 号：R971[医药卫生—药品]