In Vitro Metabolic Stability and Permeability of Gymnemagenin and Its In Vivo Pharmacokinetic Correlation in Rats - A Pilot Study
In Vitro Metabolic Stability and Permeability of Gymnemagenin and Its In Vivo Pharmacokinetic Correlation in Rats - A Pilot Study
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DOI：
10.1055/s-0042-101032
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发表时间：
2016-04-01
期刊：
影响因子：
2.7
通讯作者：
Karmakar, Sanmoy
中科院分区：
文献类型：
--
作者：
Bera, Rammohan;Kundu, Amit;Karmakar, Sanmoy
匙羹藤是传统上用于糖尿病。文献调查显示，很少有报道，特别是对大鼠肝微粒体稳定性，caco-2渗透性和外排性的关注及其与Gymnemagenin的生物利用度的相关性，Gymnemagenin是G.西尔维斯特。因此，我们的研究目的是研究体外大鼠肝微粒体稳定性和caco-2渗透性沿着与gymnemagenin外排，并建立这些体外结果与大鼠经口和静脉给药后药代动力学参数的可能相关性。使用液相色谱-串联质谱法进行大鼠肝微粒体稳定性研究，以估计培养21天后的体外固有半衰期、清除率和Caco-2渗透性，以确定从顶端到基底和从基底到顶端的表观渗透性，以及裸藻皂苷元的外排率。一种灵敏、稳健的生物分析方法得到验证，并成功应用于测定裸裸子菜皂苷元的血浆暴露量。体外大鼠肝微粒体稳定性表明，裸子菜苷元代谢迅速，表观和内在半衰期短（类似于7分钟），内在清除率高，即，190.08 μ L/min/mg微粒体。Caco-2研究的结果表明渗透性较差（1.31 × 10（-6）cm/sec），外排率非常高。药代动力学研究显示，裸甲皂苷元的口服生物利用度较差（约为14%），并且发现其在大鼠中具有短半衰期和高清除率。我们的体外研究结果表明，代谢稳定性低，Caco-2渗透性差，外排率高，这可能与观察到的大鼠口服生物利用度差有关。
Gymnema sylvestre is traditionally used for diabetes mellitus. A literature survey revealed very few reports, particularly on rat liver microsomal stability, caco-2 permeability and efflux concerns and its correlation with the bioavailability of gymnemagenin, an important component of G. sylvestre. Therefore, the objective of our study was to investigate the in vitro rat liver microsomal stability and caco-2 permeability along with the efflux of gymnemagenin and establish a probable correlation of these in vitro findings with pharmacokinetic parameters after oral and intravenous administration in rats. Rat liver microsomal stability studies to estimate the in vitro intrinsic half-life, clearance, and Caco-2 permeability after 21 days of culture to determine the apparent permeability from apical to basal and from basal to apical, and efflux ratio of gymnemagenin were performed using liquid chromatography-tandem mass spectrometry. A sensitive, robust bioanalytical method was validated and successfully applied to determine the plasma exposure of gymnemagenin. In vitro rat liver microsomal stability demonstrated that gymnemagenin metabolizes rapidly with a short apparent and intrinsic half-life (similar to 7min) and high intrinsic clearance, i.e., 190.08 mu L/min/mg of microsomes. The results of the Caco-2 study indicated a poor permeability (1.31x10(-6)cm/sec) with a very high efflux ratio. The pharmacokinetic study revealed poor oral bioavailability (similar to 14%) of gymnemagenin and it was found to have a short half-life and a high clearance in rats. Our in vitro findings indicated low metabolic stability and poor Caco-2 permeability with high efflux, which might have a role in the observed poor oral bioavailability in rats.