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Pharmacokinetics Comparison, Intestinal Absorption and Acute Toxicity Assessment of a Novel Water-Soluble Astragaloside IV Derivative (Astragalosidic Acid, LS-102)

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European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and Objectives

Astragaloside IV (AGS IV) is the most important bioactive constituent of Radix Astragali. However, its disappointing clinical application is mainly caused by its very low solubility in biologic fluids, resulting in poor bioavailability after oral administration. We recently obtained a novel water-soluble derivative of AGS IV (astragalosidic acid, LS-102) that displayed significant cardioprotective potential against hypoxia-induced injury. The objective of this study was to investigate the intestinal absorption, main pharmacokinetic parameters and acute toxicity of LS-102 in rodents compared with AGS IV.

Methods

An oral dose of LS-102 and AGS IV (20 mg/kg) was administered to Sprague-Dawley (SD) rats, and blood samples were collected at predetermined time points. The plasma concentrations were detected by a validated UHPLC-MS/MS method, and pharmacokinetic parameters were calculated using a compartmental model. In the intestinal permeability study, the transport of LS-102 across Caco-2 cell monolayers was investigated at six concentrations from 6.25 to 250 µM. Moreover, the acute toxicity of LS-102 (40–5000 mg/kg) via a single oral administration was investigated in BALB/c mice.

Results

LS-102 was rapidly absorbed, attaining a maximum concentration of 248.7 ± 22.0 ng/ml at 1.0 ± 0.5  h after oral administration. The relative bioavailability of LS-102 was twice that of AGS IV. LS-102 had a Papp (mean) of 15.72–25.50 × 10−6 cm/s, which was almost 500-fold higher than that of AGS IV, showing that LS-102 had better transepithelial permeability and could be better absorbed in the intestinal tract. The acute toxicity study showed no abnormal changes or mortality in mice treated with LS-102 even at the single high dose of 5000 mg/kg body weight.

Conclusions

Oral LS-102 produced a pharmacokinetic profile different from AGS IV with higher bioavailability, while the toxic tolerance was similar to previous estimates. Thus, we speculated that LS-102 might provide better clinical efficacy and be a potential candidate for the new drug development of Radix Astragali.

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Authors and Affiliations

  1. Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China

    Lin-Sen Qing & Li-Sheng Ding

  2. State Key Laboratory for Quality Research of Chinese Medicines, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, China

    Ting-Bo Chen, Li Chen, Pei Luo & Zhi-Feng Zhang

  3. Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu, China

    Wen-Xia Sun

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  1. Lin-Sen Qing
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Corresponding author

Correspondence to Pei Luo.

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Funding

This work was supported by the Chinese Academy of Sciences (CAS) ‘Light of West China’ Program and the Platform of Discovery, Evaluation and Transformation of Active Natural Compounds, Biological Resources Network, CAS.

Conflict of interest

The authors Lin-Sen Qing, Ting-bo Chen, Wen-Xia Sun, Li Chen, Pei Luo, Zhi-Feng Zhang and Li-Sheng Ding have no conflict of interest to declare.

Ethical approval

All animal experiments were carried out in accordance with the Institutional Guidelines and Animal Ordinance (Department of Health, Hong Kong Special Administrative Region) and approved by the Animal Ethics Committee of Macau University of Science and Technology (Macau Special Administrative Region).

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Qing, LS., Chen, TB., Sun, WX. et al. Pharmacokinetics Comparison, Intestinal Absorption and Acute Toxicity Assessment of a Novel Water-Soluble Astragaloside IV Derivative (Astragalosidic Acid, LS-102). Eur J Drug Metab Pharmacokinet 44, 251–259 (2019). https://doi.org/10.1007/s13318-018-0515-5

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