从盾叶薯蓣中提取的薯蓣皂苷元和薯蓣皂苷的体外 ADME 性质特征。
Characterization of in vitro ADME properties of diosgenin and dioscin from Dioscorea villosa.
机构信息
National Center for Natural Products Research, The University of Mississippi, University, MS, USA.
出版信息
Planta Med. 2013 Oct;79(15):1421-8. doi: 10.1055/s-0033-1350699. Epub 2013 Aug 22.
Dioscorea villosa (wild yam) is native to North America and has been widely used as a natural alternative for estrogen replacement therapy to improve women's health as well as to treat inflammation, muscle spasm, and asthma. Diosgenin and dioscin (glycoside form of diosgenin) are reported to be the pharmacologically active compounds. Despite the reports of significant pharmacological properties of dioscin and diosgenin in conditions related to inflammation, cancer, diabetes, and gastrointestinal ailments, no reports are available on ADME properties of these compounds. This study was carried out to determine ADME properties of diosgenin and dioscin and their effects on major drug metabolizing enzymes (CYP 3A4, 2D6, 2C9, and 1A2). The stability was determined in simulated gastric and intestinal fluids (SGF, pH 1.2 and SIF, pH 6.8), and intestinal transport was evaluated in Caco-2 model. Phase I and phase II metabolic stability was determined in human liver microsomes and S9 fractions, respectively. Quantitative analysis of dioscin and diosgenin was performed by UPLC-MS system. Dioscin degraded up to 28.3 % in SGF and 12.4 % in SIF, which could be accounted for by its conversion to diosgenin (24.2 %. in SGF and 2.4 % in SIF). The depletion of diosgenin in SGF and SIF was < 10 %. Diosgenin was stable in HLM but disappeared in S9 fraction with a half-life of 11.3 min. In contrast, dioscin was stable in both HLM and S9 fractions. Dioscin showed higher permeability across Caco-2 monolayer with no significant efflux, while diosgenin was subjected to efflux mediated by P-glycoprotein. Diosgenin and dioscin inhibited CYP3A4 with IC50 values of 17 and 33 µM, respectively, while other CYP enzymes were not affected. In conclusion, dioscin showed better intestinal permeability. Conversion of dioscin to diosgenin was observed in both gastric and intestinal fluids. No phase I metabolism was detected for both compounds. The disappearance of diosgenin in S9 fraction indicated phase II metabolism.
野山药原产于北美，被广泛用作雌激素替代疗法的天然替代品，以改善女性健康，治疗炎症、肌肉痉挛和哮喘。薯蓣皂苷元和薯蓣皂苷（薯蓣皂苷的糖苷形式）据报道是具有药理活性的化合物。尽管有报道称薯蓣皂苷元和薯蓣皂苷在与炎症、癌症、糖尿病和胃肠道疾病相关的情况下具有显著的药理特性，但尚无关于这些化合物的吸收、分布、代谢和排泄（ADME）特性的报道。本研究旨在确定薯蓣皂苷元和薯蓣皂苷的 ADME 特性及其对主要药物代谢酶（CYP3A4、2D6、2C9 和 1A2）的影响。在模拟胃液（SGF，pH1.2）和模拟肠液（SIF，pH6.8）中测定稳定性，并在 Caco-2 模型中评估肠转运。在人肝微粒体和 S9 部分分别测定 I 相和 II 相代谢稳定性。用 UPLC-MS 系统定量分析薯蓣皂苷元和薯蓣皂苷。薯蓣皂苷在 SGF 中降解了 28.3%，在 SIF 中降解了 12.4%，这可以归因于其转化为薯蓣皂苷（SGF 中为 24.2%，SIF 中为 2.4%）。薯蓣皂苷在 SGF 和 SIF 中的耗竭率均<10%。薯蓣皂苷在 HLM 中稳定，但在 S9 部分消失，半衰期为 11.3 分钟。相比之下，薯蓣皂苷在 HLM 和 S9 部分均稳定。薯蓣皂苷在 Caco-2 单层中的透过性较高，没有明显的外排，而薯蓣皂苷则受到 P-糖蛋白介导的外排。薯蓣皂苷元和薯蓣皂苷对 CYP3A4 的抑制 IC50 值分别为 17 和 33µM，而对其他 CYP 酶没有影响。总之，薯蓣皂苷表现出更好的肠道通透性。在胃和肠液中均观察到薯蓣皂苷向薯蓣皂苷元的转化。两种化合物均未检测到 I 相代谢。薯蓣皂苷在 S9 部分的消失表明存在 II 相代谢。
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