万古霉素健康人体生理药动学模型建立及其组织分布特征预测  

Development of physiologically based pharmacokinetic modeling of vancomycin in healthy populations and tissue distribution prediction

作　　者：杜海燕[1] 陈涛 张文鹏 谭莉[1] 李正 刘文芳[1] 林阳[1] 庄笑梅 DU Hai-yan;CHEN Tao;ZHANG Wen-peng;TAN Li;LI Zheng;LIU Wen-fang;LIN Yang;ZHUANG Xiao-mei(Department of Pharmacy,Beijing Anzhen Hospital of Capital Medical University,Beijing 100029,China;PharmoGo,Co.,Ltd.,Shanghai 200120,China;State Key Laboratory of Toxicology and Medical Countermeasures,Institute of Pharmacology and Toxicology,Academy of Military Medical Sciences,Academy of Military Sciences,Beijing 100850,China)

机构地区：[1]首都医科大学附属北京安贞医院药事部,北京100029 [2]上海凡默谷信息技术有限公司,上海200120 [3]军事科学院军事医学研究院毒物药物研究所抗毒药物与毒理学国家重点实验室,北京100850

出　　处：《中国药理学与毒理学杂志》2018年第3期201-207,共7页Chinese Journal of Pharmacology and Toxicology

基　　金：国家科技重大专项项目(2018ZX09711003-006);国家科技重大专项项目(2017ZX09304017);首都医科大学基础-临床科研合作基金项目(15JL57)~~

摘　　要：目的应用"自下而上"方法建立万古霉素在美国青年人的生理药代动力学(PBPK)模型,以美国青年人尿液排泄和中国青年人静滴给药后的药动学(PK)进行验证,进而预测其在人体各器官组织特别是毒性靶器官肾中的分布特征。方法以"万古霉素"、"log P"、"p Ka"、"pharmacokinetics"为关键词,检索中国知网、Science Direct和Pub Med等数据库关于万古霉素理化常数及人体PK相关文献,采用Gastro PlusTM建立、优化并验证了万古霉素静滴给药的人体PBPK模型,通过药代参数倍数误差评价模型有效性。采用脏器构成模型结合药物特异性参数,应用透膜限速模型预测万古毒素在各器官组织中的分布特征。结果建立的美国青年人万古霉素PBPK模型中预测的药物浓度-时间(药-时)曲线与实测曲线吻合度良好(r2=0.914)。应用该模型成功预测美国青年人尿排泄曲线及中国青年人静滴万古霉素后药-时曲线,与实测吻合度良好(r2=0.936)。所建立的PBPK模型预测万古霉素在中国青年人各器官的处置特征结果表明,万古霉素在肝和心等组织中浓度低于血浆浓度,但在肾和肾小管中浓度高于血浆浓度,其中在肾中具有明显的滞后效应,肾小管中药物浓度远远高于血浆中40~50倍。结论首次建立了基于PBPK的万古霉素人体PK模型,并预测了万古霉素组织器官中的分布特征,为深入研究万古霉素的肾毒性机制及临床评估提供参考。OBJECTIVE To establish a whole-body physiologically based pharmacokinetic（PBPK）model of vancomycin for healthy adults based on literature and to predict tissue distribution characters of vancomycin. METHODS The literature from CNKI, Science Direct, Pub Med and other databases was searched for relevant information on vancomycin by using ＂vancomycin＂, ＂logP＂, ＂pKa＂ and ＂pharmacokinetics＂ as keywords. Consolidated information was incorporated into a validated PBPK vancomycin model for intravenous infusion administration of vancomycin among American young populations.Vancomycin partitions in 14 tissue compartments were described by permeability-limited compartments.Tissue distribution of vancomycin was predicted using the established PBPK model. RESULTS The plasma concentration-time curves of vancomycin among American young populations predicted by the PBPK model fitted well with the measured value（r^2=0.914）. This PBPK model accurately predicted the observed urinary excretion profiles in American young populations and the observed plasma concentration profiles and pharmacokinetics of intravenous infusion administration of vancomycin among the Chinese counterparts were predicted correctly as well（r^2=0.936）. The PBPK model demonstrated that vancomycin was extensively distributed in most tissues. The concentrations of vancomycin in the kidney and renal tubule were higher than those in plasma, while the concentrations in the liver or heart were lower than those in plasma. Especially, the concentration in renal tubules was about 40-50 times higher than that in plasma. CONCLUSION PBPK modelling incorporating literature data is able to correctly predict vancomycin pharmacokinetics in Chinese young populations. This is the first time that the concentrations of vancomycin in the kidney and renal tubule have been found to be much higher than those in plasma. This study can contribute to further studies on vancomycin induced nephrotoxicity.

关 键 词：生理药动学模型 万古霉素 组织分布 肾损伤 

分 类 号：R969.1[医药卫生—药理学]