Abstract
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 paeoniflorin 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.
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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).
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Supplementary information is available at the Acta Pharmacologica Sinica's website.
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Supplementary Information Appendix S1
Brief Description of Method for Preparation of XueBiJing Injection (DOC 73 kb)
Supplementary Information, Figure S1
Mean plasma concentrations of oxypaeoniflorin (6) and albiflorin (4) over time in human (male and female) subjects receiving an intravenous infusion of XueBiJing injection (DOC 136 kb)
Supplementary Information Table S1
Plasma Pharmacokinetics and Renal Excretion of Paeoniflorin (5) on Day 7 in Six Male Human Subjects Receiving Multiple Intravenous Infusion of XueBiJing Injection (DOC 41 kb)
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Cheng, C., Lin, Jz., Li, L. et al. Pharmacokinetics and disposition of monoterpene glycosides derived from Paeonia lactiflora roots (Chishao) after intravenous dosing of antiseptic XueBiJing injection in human subjects and rats. Acta Pharmacol Sin 37, 530–544 (2016). https://doi.org/10.1038/aps.2015.103
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DOI: https://doi.org/10.1038/aps.2015.103
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