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

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 P (mean) of 15.72-25.50 × 10 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.