中药复方药物动力学数学模型的建立及对补阳还五汤的研究

【作者】 贺福元；

【导师】 罗杰英；

【作者基本信息】 成都中医药大学 ， 中药学， 2006， 博士

【摘要】 中药复方药物动力学（pharmacokinetic of the prescription of TCM）是在传统药物动力学基础上发展起来，主要针对中药或中药复方进行的药物动力学。目前传统药物动力学是建立在单成分（指标），以房室模型研究为基础的，以中央室（血液室）参数分析为核心，重在阐明药物在机体内四大转运过程的量变规律。适合单成分、单模型、单室分析（中央室）的药物动力学研究。中药及复方为多成分体系，体现多模型，多靶点霰弹效应，用传统的药物动力学方法研究中药复方必然产生：①适应多成分体系药物动力学研究的数学模型问题；②多成分的含量测定问题；③血液成分干扰的消除问题；④中药复方药物动力学参数信息的处理问题。本文针对这四个问题，从理论和实验两方进行了中药复方药物动力学的探讨： 理论方面： 1．论证和创立了适应中药复方多成分的药物动力学数学模型：总量统计矩模型。 2．将总量统计矩原理与指纹图谱的多信息分析相结合，创立了中药指纹图谱快速的定性定量分析方法：总量统计矩法，该法能克服相似度法难以对峰的叠加和消除处理的缺陷；该法不以指纹图谱的特征峰分析为信息单元，不采用峰峰相应的多维向量分析法，而是将指纹图谱看成是由众多函数曲线叠加而成的概率密度函数曲线，用统计学的方法来分析指纹图谱的内在特征，用AUC_T进行定量，用AUCPW_T、MIVV_T、VIVV_T进行定性分析。 3．将指纹图谱总量统计矩分析与药物动力学二维向量关联，推导和证明了二维向量的总量统计矩参数的计算式，确立了用AUC_T、（?）_T，i=2、σ²_Tλ，i=2（VIVV_T）、MRT_T、σ²_Tt，i=2（VRT_T）来刻画二维向量曲线特征。 4．将总量统计矩原理与实验结果计算结合起来，推导出二维向量总量统计矩的计算公式，应用EXCEL软件，自编程序进行药物动力学参数计算。用Visual basic编程计算取样实验点与模型参数对梯形法面积与积分法面积之比的关系，确定最小取样点为9。 实验方面： 5．用传统的药物动力学方法研究了补阳还五汤及三大有效部位中黄芪甲苷、芍药苷、苦杏仁苷、川芎嗪、阿魏酸的药物动力学。用总量统计矩法对五个已知成分进行计算得药物动力学总量统计矩参数为：AUC为613.5mg·min·mL^-1、MRT为1135.1min、VRT为2.813×10⁵min²、CL为0.01007mL·min^-1·kg^-1。说明总量统计矩能整合不同成分不同药物动力学参数，表达多成分的药动力学行为。 6．按方法学要求对补阳还五汤的指纹图谱测定进行了精密度、峰积分阈值、对照药材的线性关系、药材进行加样回收率实验，血样加样回收率实验，证明总量统计矩法能适应多成分指纹图谱的药物及血液样品的分析。 7．运用指纹图谱与药物动力学相关联建立二维向量总量统计矩模型，以补阳还五汤为模型进行雄免药物动力学研究，总量统计矩参数：AUCPW_T=8.672×10⁷μv·sec·h·min·kg^-1·mL^-1、∑λ_j.A_j=3.338×10⁹kg^-1·mL^-1μv·sec·h·min²·kg^-1·mL^-1、MIVV_T=38.49min、∑σ_1，j²·A_1，j=3.876×10⁷μv·sec·h·min³·kg^-1·mL^-1、VIVV_T=971更多还原

【Abstract】 The pharmacokinetics of the prescription of the traditional Chinese medicine （PPTCM） has been developing to aim directly to study on the pharmacokinetics of the traditional Chinese materials and its constitutional prescriptions.on the basis of pharmacokinetic theories. It occurs to us that there are four challenge problems to study on the PPTCM, with the present pharmacokinetic methods that is established on compartmental models, parameter analyses of center compartment and satisfied with single compound. The four problems are: ①how to establish the mathematic models satisfied with the multicomponent system; ② how to determinate simultaneously multicomponents; ③how to eliminate the interferences form blood ingredients:④ how to deal with information of the PPTCM. For that the theoretical and experimental studies on PPTCM has been carried out.Theoretically:1.To have elucidated and establish the mathemathic models of the PPTCM: Total Quantum Statistic Moment（TQSM）.2.To have established the Total Quantum Statistic Moment Analyses of the fingerprint（TQSMAF） that has of qualitative and quantitative immediate analyses, in combination of the TQSM with fingerprint. The TQSMAF, to overcome shortcoming of similarity analyses that can not be calculated the peak area with addition and substraction, independs on the analyses of character peaks to be transformed multidimension vectors with peak vs. peaks. It has been considered the fingerprint as probability density ruction added by multicomponent Gauss curves to be dealt with the curve characters of the fingerprint with statistics, as a result that AUC_T can be applied to quantitative analyses, whereas AUCPW_T、 MIVV_T、VIVV_T can be used to qualitative analyses.3 To have elucidated and establish the 2-Dimension Vector Total Quantum Statistic Moment（2-DVTQSM） models of the PPTCM, in combination of fingerprint with pharmacokinetics; To obtain the parameter expressions of 2-dimension vectors;To describe the curve character with AUC_T, （λ|-）_T,i=2,Ε²_Tλ,i=2（VIVV_T）, MRTt, Ε²_Tt,i=2（VRT_T） .4. To have elucidated out the calculation formulae for 2-Dimension Vector Total Quantum Statistic Moment models ,in combination with pharmacokinetic experiment that can be calculated by ourselves editing programming with EXCEL software ; To calculate the ratio between the area under the curve with trapezoid and integration by ourselves editing programs with Visual basic software to determinate 9 as minimum sampling experiment point.Experimentally:5. To have studied on the pharmacokinetic parameters of astragalalV, peoniflorin, amygdaloside, tetramethylpyrazine ferulaic acid in the Buyanghuanwu Deco-ction（BYHWD） and available fractions with present pharmacokinetics, to deal with the TQSM parameters of the five available ingredients that results show AUC as 613.5 mg·min·mL^-1; MRT as 135.1 min; VRT as 2.813×10⁵ min²; CL as 0.01007 mL·min^-1·kg^-1. The results testified the TQSM could conform single ingredient parameters to bring about total pharmacokinetic parameters, to explain the更多还原