中药生物药剂学分类系统的研究和发展思路探讨
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摘要
针对生物药剂学分类系统(biopharmaceutics classification system,BCS)是依据药物溶解性和渗透性对药物进行分类并提供药物生物利用度-吸收关联分析的一种科学框架或方法,课题组基于中药多成分多靶点的特色及BCS的理念、方法和技术,提出中药生物药剂学分类系统(biopharmaceutics classification system of Chinese materia medica,CMMBCS)并以经典方为基础进行了研究和数据积累。结合前期研究成果,在CMMBCS概念和框架下提出进一步的发展思路:在研究过程中,省略多成分环境的复杂相互作用的中间环节影响,直接关注复方成分发挥主要临床疗效的成分吸收研究,或从代谢、药效通路和吸收原理等方面反推吸收成分和数据,从单成分和复方2个方面进行研究,全面评价中药复方及组方中药的吸收属性;在研究路径中,充分考虑中药发挥药效的不同途径,并重点以吸收入血途径开展CMMBCS分类归属与树立规律;在具体方法上,拓展应用网络药理学及分子对接技术筛选中药复方指标成分和通过PBPK模型研究体内吸收,反向推理计算CMMBCS吸收参数,并通过药效或吸收途径研究修正中药复方CMMBCS分类归属。通过对CMMBCS基础理论确立、以药效导向的研究思路补充及现代成熟中药方法学的拓展应用,在研究基础上对CMMBCS的理论框架和研究方法学进行了系统完善。
The biopharmaceutics classification system( BCS) is a scientific framework or method for classifying drugs based on drug solubility and permeability,which can be used to provide drug bioavailability-absorption correlation analysis. Based on the characteristics of multi-component and multi-target of traditional Chinese medicine( TCM) as well as the concept,method and technology of BCS,the research group proposed biopharmaceutics classification system of Chinese materia medica( CMMBCS) and carried out research and data accumulation of classical prescriptions. Based on the previous research results,further development ideas under the CMMBCS concept and framework were further proposed in this study. In the course of research,the influence of the intermediate links of the complex interactions of the multi-component environment was omitted,and the component absorption studies on the main clinical effects of prescription ingredients were directly concerned,or the components and data were reversely extracted from the aspects of metabolism,pharmacodynamic pathways and absorption principles. Studies were conducted from two aspects( single component and compound prescription) to comprehensively evaluate the absorption properties of TCM compound. In the research path,the different ways in which Chinese medicine could exert its efficacy were fully considered,and CMMBCS classification and establishment rules were clarified mainly by focusing on the absorption pathway into the blood. Specifically,the network pharmacology and molecular docking technology were used to screen the compound index components of TCM; the absorption rules were studied by the physiologically based pharmacokinetic models and the absorption parameters of CMMBCS were calculated by reverse reasoning. Then the CMMBCS classification of TCM prescription was corrected by studying the efficacy or absorption pathway. In this paper,the theoretical framework and research methodology of CMMBCS were systematically improved based on the establishment of CMMBCS basic theory,the supplementary of drug-oriented research ideas and the application of modern mature Chinese medicine methodology.
The biopharmaceutics classification system( BCS) is a scientific framework or method for classifying drugs based on drug solubility and permeability,which can be used to provide drug bioavailability-absorption correlation analysis. Based on the characteristics of multi-component and multi-target of traditional Chinese medicine( TCM) as well as the concept,method and technology of BCS,the research group proposed biopharmaceutics classification system of Chinese materia medica( CMMBCS) and carried out research and data accumulation of classical prescriptions. Based on the previous research results,further development ideas under the CMMBCS concept and framework were further proposed in this study. In the course of research,the influence of the intermediate links of the complex interactions of the multi-component environment was omitted,and the component absorption studies on the main clinical effects of prescription ingredients were directly concerned,or the components and data were reversely extracted from the aspects of metabolism,pharmacodynamic pathways and absorption principles. Studies were conducted from two aspects( single component and compound prescription) to comprehensively evaluate the absorption properties of TCM compound. In the research path,the different ways in which Chinese medicine could exert its efficacy were fully considered,and CMMBCS classification and establishment rules were clarified mainly by focusing on the absorption pathway into the blood. Specifically,the network pharmacology and molecular docking technology were used to screen the compound index components of TCM; the absorption rules were studied by the physiologically based pharmacokinetic models and the absorption parameters of CMMBCS were calculated by reverse reasoning. Then the CMMBCS classification of TCM prescription was corrected by studying the efficacy or absorption pathway. In this paper,the theoretical framework and research methodology of CMMBCS were systematically improved based on the establishment of CMMBCS basic theory,the supplementary of drug-oriented research ideas and the application of modern mature Chinese medicine methodology.
引文
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[2] Amidon G L,Hans L,Shah V P,et al. A theoretical basis for a biopharmaceutic drug classification:the correlation of in vitro drug product dissolution and in vivo bioavailability[J]. Pharm Res,1995,12(3):413.
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[5] Yu L X,Lipka E,Crison J R,et al. Transport approaches to the biopharmaceutical design of oral drug delivery systems:prediction of intestinal absorption[J]. Adv Drug Deliv Rev,1996,19(3):p359.
[6] Keith C T,Borisy A A,Stockwell B R. Innovation:multicomponent therapeutics for networked systems[J]. Nat Rev Drug Discov,2005,4(1):71.
[7] Zhang J,Liu D,Huang Y,et al. Biopharmaceutics classification and intestinalabsorption study of apigenin[J]. Int J Pharm,2012,436(1/2):311.
[8] Smetanova L,Stetinova V,Kholova D,et al.Caco-2 cells and biopharmaceutics classification system(BCS)for prediction of transepithelial transport of xenobiotics(model drug:caffeine)[J].Neuro Endocrinol Lett,2009,30 Suppl 1:101.
[9]赵珺睿,任晓亮,王萌.荷叶药材中荷叶碱生物药剂学分类系统研究[J].中国中药杂志,2018,43(3):511.
[10]陈敏燕,金芝贵,吴飞华,等.应用人工神经网络预测药物的生物药剂学分类[J].中国药学杂志,2010(9):669.
[11]孙乐.基于BCS系统的in silico/in vitro模型评价药物及制剂的BA/BE[D].沈阳:沈阳药科大学,2013.
[12]刘曼,张文萍,张丽娜,等.基于生物药剂学分类系统的口服固体速释制剂生物豁免[J].中国新药杂志,2016(5):532.
[13]叶雯,王永禄,李学明.生物药剂学分类系统在难溶性药物处方设计中的应用[J].中国医院药学杂志,2013,33(7):568.
[14]平其能.中药成分的胃肠转运与剂型设计[M].北京:化学工业出版社,2010.
[15]刘丹,郁丹红,孙娥,等.中药组分与组分生物药剂学分类系统构建[J].中国中药杂志,2012,37(19):2997.
[16]柯仲成,林传燕,贾晓斌.基于代表性成分辨识的中药组分整体生物药剂学性质表征探讨[J].中国中药杂志,2018,43(23):4592.
[17]刘洋,隗丽,董玲,等.多成分体系下中药生物药剂学分类系统的构建分析[J].中国中药杂志,2014,39(23):4479.
[18] Oh D M,Curl R L,Amidon G L. Estimating the fraction dose absorbed from suspensions of poorly soluble compounds in humans:a mathematical model[J]. Pharm Res,1993,10(2):264.
[19]王耘,史新元,乔延江.中药复杂性研究的内容与方法[J].中国天然药物,2005(5):262.
[20]隗丽.基于黄连降糖作用的生物药剂学分类系统研究[D].北京:北京中医药大学,2016.
[21]苏元元,付宇,李楠楠,等.三种达玛烷型皂苷的生物药剂学分类及吸收机制研究[J].中国现代中药,2018,20(9):1150.
[22] Wood J,Syarto J,Letterman H. Improved holder for intrinsic dissolution rate studies[J]. J Pharm Sci,2010,54(7):1068.
[23] Zakeri-Milani P,Barzegar-Jalali M,Azimi M,et al. Biopharmaceutical classification of drugs using intrinsic dissolution rate(IDR)and rat intestinal permeability[J]. Eur J Pharm Biopharm,2009,73(1):0.
[24] Lawrence X Y,Alan S C,Gordon L A,et al. Feasibility studies of utilizing disk intrinsic dissolution rate to classify drugs[J]. Int J Pharm,2004,270(1):221.
[25]隗丽,汪国鹏,董玲,等.中药生物药剂学分类系统的多成分溶出评价方法在葛根芩连片中的应用[J].中国中药杂志,2014,39(23):4494.
[26]尹秀文,王子禹,潘孟,等.中药生物药剂学分类系统中多成分环境下小檗碱的特性溶出速率研究[J].中国中药杂志,2018,43(11):2269.
[27]付晓峰,柯学.口服药物溶出技术与体内外相关性的研究进展[J].药学与临床研究,2012,20(2):142.
[28]操锋,平其能,陈军,等.口服前药研究:机遇与挑战[J].药学学报,2008,43(4):343.
[29]李光华.口服药物吸收的研究进展[J].天津药学,2014,26(2):69.
[30] Lennerns H. Human jejunal effective permeability and its correlation with preclinical drug absorption models[J]. J Pharm Pharmacol,1997,49(7):627.
[31] Salphati L,Childers K,Pan L,et al. Evaluation of a single-pass intestinal-perfusion method in rat for the prediction of absorption in man[J]. J Pharm Pharmacol,2001,53(7):1007.
[32] Dezani T M,Dezani A B,Junior J B,et al. Single-pass intestinal perfusion(SPIP)and prediction of fraction absorbed and permeability in humans:a study with antiretroviral drugs[J]. Eur J Pharm Biopharm,2016,104:131.
[33]刘洋,尹秀文,王子禹,等.黄连提取物的中药生物药剂学分类系统研究[J].中国中药杂志,2017,42(21):4127.
[34] Johnson K C,Swindell A C. Guidance in the setting of drug particle size specifications to minimize variability in absorption[J].Pharm Res,1996,13(12):1795.
[35] Curatolo W. Physical chemical properties of oral drug candidates in the discovery and exploratory development settings[J]. Pharm Sci Tech Today,1998,1(9):387.
[36] Fagerholm U. Prediction of human pharmacokinetics-gastrointestinal absorption[J]. J Pharm Pharmacol,2007,59(7):905.
[37] Li H,Dong L,Liu Y,et al. Biopharmaceutics classification of puerarin and comparison of perfusion approaches in rats[J]. Int J Pharm,2014,466(1/2):133.
[38]侯成波,汪国鹏,张强,等.中药生物药剂学分类系统中多成分环境对葛根素溶解度的影响[J].中国中药杂志,2014,39(23):4499.
[39]刘洋,王刚,董玲,等.中药生物药剂学分类系统中多成分环境对葛根素渗透性的影响[J].中国中药杂志,2014,39(23):4505.
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