Journal
PHYTOMEDICINE
Volume 53, Issue -, Pages 243-251Publisher
ELSEVIER GMBH
DOI: 10.1016/j.phymed.2018.09.019
Keywords
Astragalosidic acid; Astragaloside IV derivative; Pharmacokinetics; Bioavailability; UPLC-MS/MS
Categories
Funding
- Chinese Academy of Sciences (CAS) 'Light of West China' Program
- Platform of Discovery, Evaluation and Transformation of Active Natural Compounds, Biological Resources Network, CAS
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Background: Astragalosidic acid (LS-102) is a new water-soluble derivative of astragaloside IV - a major effective component isolated from the Chinese herb Astragali Radix. Our previous study showed that LS-102 exhibited potent cardiovascular activity. Purpose: The objective of this study was to investigate the pharmacokinetic properties of LS-102 after single-dose, oral administration in beagle dogs by developing and validating an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. Method and result: The chromatographic separation was performed on a Acquity HSS C-18 column (100 mm x 2.1 mm, 1.8 mu m) by a gradient elution using a mobile phase consisting of water and acetonitrile at a flow rate of 0.35 ml/min. The analytes were detected with a triple quadrupole tandem mass spectrometry in multiple reaction monitoring mode. Method validation revealed a wide linearity over the range of 2.0-10,000 ng/ml together with satisfactory intra- and inter-day precision, accuracy, and recovery. Stability testing showed that LS-102 spiked into dog plasma was stable for 4 h at room temperature, for up to 2 weeks at -80 degrees C, and during three freeze-thaw cycles. The method was effectively and successfully applied to the pharmacokinetics of LS-102 after oral administration (5, 10 and 20 mg/kg) to beagle dogs. Peak plasma concentrations are attained within approximately 2 h after oral administration with a half-life ranging from 1.55 h to 4.49 h. The plasma concentration-time curve of LS-102 after oral administration presents the phenomenon of a double-peak absorption phase. The peak concentration and area under the concentration-time curve of LS-102 seemed to increase with the increasing doses proportionally, that suggesting linear pharmacokinetics in dogs. Meanwhile, the doxorubicin (Dox)-injured H9c2 cell model was prepared by incubating the cells in 1 mu M Dox for 24 h. MTT assay and LDH release measurement showed that LS-102 protected against Dox-induced cardio-myocyte death. Conclusion: The obtained results may help to guide the further pre-clinical research of LS-102 as a potentially novel cardioprotective agent.
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