Qing Lin-Sen, Chen Ting-Bo, Sun Wen-Xia, Chen Li, Luo Pei, Zhang Zhi-Feng, Ding Li-Sheng
Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China.
State Key Laboratory for Quality Research of Chinese Medicines, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, China.
Eur J Drug Metab Pharmacokinet. 2019 Apr;44(2):251-259. doi: 10.1007/s13318-018-0515-5.
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.
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.
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.
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.
黄芪甲苷（AGS IV）是黄芪最重要的生物活性成分。然而，其令人失望的临床应用主要是由于其在生物流体中的溶解度极低，导致口服给药后生物利用度差。我们最近获得了一种新型的AGS IV水溶性衍生物（黄芪酸，LS - 102），它对缺氧诱导的损伤显示出显著的心脏保护潜力。本研究的目的是研究与AGS IV相比，LS - 102在啮齿动物中的肠道吸收、主要药代动力学参数和急性毒性。
给Sprague - Dawley（SD）大鼠口服剂量为20 mg/kg的LS - 102和AGS IV，并在预定时间点采集血样。通过经过验证的超高效液相色谱 - 串联质谱（UHPLC - MS/MS）方法检测血浆浓度，并使用房室模型计算药代动力学参数。在肠道通透性研究中，研究了LS - 102在6.25至250 μM的六个浓度下跨Caco - 2细胞单层的转运情况。此外，在BALB/c小鼠中研究了单次口服给予LS - 102（40 - 5000 mg/kg）的急性毒性。
LS - 102吸收迅速，口服给药后1.0±0.5小时达到最大浓度248.7±22.0 ng/ml。LS - 102的相对生物利用度是AGS IV的两倍。LS - 102的P（平均值）为15.72 - 25.50×10 cm/s，几乎比AGS IV高500倍，表明LS - 102具有更好的跨上皮通透性，并且在肠道中可以更好地吸收。急性毒性研究表明，即使在5000 mg/kg体重的单次高剂量下，用LS - 102处理的小鼠也没有出现异常变化或死亡。
口服LS - 102产生了与AGS IV不同的药代动力学特征，生物利用度更高，而毒性耐受性与先前的估计相似。因此，我们推测LS - 102可能提供更好的临床疗效，并且是黄芪新药开发的潜在候选药物。
