Pharmacokinetics and disposition of monoterpene glycosides derived from Paeonia lactiflora roots （Chishao） after intravenous dosing of antiseptic XueBiJing injection in human subjects and rats  

作　　者：Chen CHENG Jia-zhen LIN Li LI Jun-ling YANG Wei-wei JIA Yu-hong HUANG Fei-fei DU Feng-qing WANG Mei-juan LI Yan-fen LI Fang XU Na-ting ZHANG Olajide E. OLALEYE Yan SUN Jian LI Chang-hai SUN Gui-ping ZHANG Chuan LI 

机构地区：[1]Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China [2]Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China [3]University of Chinese Academy of Sciences, Shanghai 201203, China [4]Second Affiliated Hospital, Tianjin University of Traditional Chinese Medicine, Tianjin 300150, China [5]Tianjin Chasesun Pharmaceutical Co, Ltd, Tianjin 301700, China

出　　处：《Acta Pharmacologica Sinica》2016年第4期530-544,共15页中国药理学报（英文版）

基　　金：Acknowledgements This work was funded by grants from the National Science ＆ Technology Major Project of China ＇Key New Drug Creation and Manufacturing Program＇ （2009ZX09304-002 and 2011ZX09201-201-23）, the National Science Foundation of China for Distinguished Young Scholars （30925044）, the National Basic Research Program of China （2012CB518403）, the National Natural Science Foundation of China （81503345）, and the China Postdoctoral Science Foundation funded project （2014M560169）.

摘　　要：Aim： Monoterpene glycosides derived from Paeonia lactiflora roots （Chishao） are believed to be pharmacologically important for the antiseptic herbal injection XueBiJing. This study was designed to characterize the pharmacokinetics and disposition of monoterpene glycosides. Methods： Systemic exposure to Chishao monoterpene glycosides was assessed in human subjects receiving an intravenous infusion and multiple infusions of XueBiJing injection, followed by assessment of the pharmacokinetics of the major circulating compounds. Supportive rat studies were also performed. Membrane permeability and plasma-protein binding were assessed in vitro. Results： A total of 18 monoterpene glycosides were detected in XueBiJing injection （content levels, 0.001-2.47 mmol/L）, and paeoniflorin accounted for 85.5% of the total dose of monoterpene glycosides detected. In human subjects, unchanged paeoniflorin exhibited considerable levels of systemic exposure with elimination half-lives of 1.2-1.3 h; no significant metabolite was detected. Oxypaeoniflorin and albiflorin exhibited low exposure levels, and the remaining minor monoterpene glycosides were negligible or undetected. Glomerular-filtration-based renal excretion was the major elimination pathway of paeoniflorin, which was poorly bound to plasma protein. In rats, the systemic exposure level of paeoniflorJn increased proportionally as the dose was increased. Rat lung, heart and liver exposure levels of paeoniflorin were lower than the plasma level, with the exception of the kidney level, which was 4.3-fold greater than the plasma level; brain penetration was limited by the poor membrane permeability. Conclusion： Due to its significant systemic exposure and appropriate pharmacokinetic profile, as well as previously reported antiseptic properties, paeoniflorin is a promising XueBiJing constituent of therapeutic importance.Aim： Monoterpene glycosides derived from Paeonia lactiflora roots （Chishao） are believed to be pharmacologically important for the antiseptic herbal injection XueBiJing. This study was designed to characterize the pharmacokinetics and disposition of monoterpene glycosides. Methods： Systemic exposure to Chishao monoterpene glycosides was assessed in human subjects receiving an intravenous infusion and multiple infusions of XueBiJing injection, followed by assessment of the pharmacokinetics of the major circulating compounds. Supportive rat studies were also performed. Membrane permeability and plasma-protein binding were assessed in vitro. Results： A total of 18 monoterpene glycosides were detected in XueBiJing injection （content levels, 0.001-2.47 mmol/L）, and paeoniflorin accounted for 85.5% of the total dose of monoterpene glycosides detected. In human subjects, unchanged paeoniflorin exhibited considerable levels of systemic exposure with elimination half-lives of 1.2-1.3 h; no significant metabolite was detected. Oxypaeoniflorin and albiflorin exhibited low exposure levels, and the remaining minor monoterpene glycosides were negligible or undetected. Glomerular-filtration-based renal excretion was the major elimination pathway of paeoniflorin, which was poorly bound to plasma protein. In rats, the systemic exposure level of paeoniflorJn increased proportionally as the dose was increased. Rat lung, heart and liver exposure levels of paeoniflorin were lower than the plasma level, with the exception of the kidney level, which was 4.3-fold greater than the plasma level; brain penetration was limited by the poor membrane permeability. Conclusion： Due to its significant systemic exposure and appropriate pharmacokinetic profile, as well as previously reported antiseptic properties, paeoniflorin is a promising XueBiJing constituent of therapeutic importance.

关 键 词：herbal injection XUEBIJING Paeonia lactiflora roots Chishao monoterpene glycosides paeoniflorin PHARMACOKINETICS DISPOSITION 

分 类 号：S859.796[农业科学—临床兽医学] TQ637[农业科学—兽医学]