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首页> 外文期刊>RSC Advances >Pre-clinical pharmacokinetic and pharmacodynamic modelling study of 4-hydroxyisoleucine using validated ultra-performance liquid chromatography-tandem mass spectrometry
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Pre-clinical pharmacokinetic and pharmacodynamic modelling study of 4-hydroxyisoleucine using validated ultra-performance liquid chromatography-tandem mass spectrometry

机译：使用验证的超高效液相色谱 - 串联质谱法临床前药代动力学和4-羟基异氨酸的药效模型研究

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A reliable and sensitive ultra-performance liquid chromatography-tandem mass spectrometry-based method has been developed for the estimation of 4-hydroxyisoleucine (4-HI), a potent insulinotropic and hypolipidemic agent. The extraction of 4-HI from plasma was accomplished by the protein precipitation technique using L -isoleucine as an internal standard. The separation of analytes was achieved with a mobile phase consisting of acetonitrile and 0.1% formic acid in an isocratic flow system on a BEH Shield RP-18 column (150 mm × 2.1 mm, 1.7 μm). 4-HI and L -isoleucine were detected using an electrospray ionization (ESI) ion source, using multiple reaction monitoring (MRM) in positive ion mode. The precursor to product ion transitions of 4-HI and L -isoleucine were found at m / z values of 148.19 > 74.02 and 132.17 > 69.04, respectively. As per the guidelines for bioanalytical methods, all validation parameter results were within the acceptable range. The method exhibited a robust and reproducible linearity range of 1–5000 ng mL ~(?1) with a coefficient of regression of 0.9999. The method was successfully applied for the estimation of pharmacokinetic parameters after oral administration of 4-HI (10 mg kg ~(?1) ) in Wistar rats, by using Thoth Pro (version: 4.3) software. Herein, the two-compartment model was statistically fitted based on AIC and SBC values for evaluation of the pharmacokinetic parameters of 4-HI. Pharmacodynamic studies were also performed by measuring the levels of triglyceride and total cholesterol, and showed that the pharmacokinetic and pharmacodynamic data of 4-HI correlated with each other.
机译：已经开发了一种可靠敏感的超高性能液相色谱 - 串联质谱法用于估计4-羟基异氨酸（4-HI），有效的胰岛素和低血脂剂。通过使用L-氨基氨酸作为内标，通过蛋白质沉淀技术完成血浆中4-Hi的提取。通过在AB屏蔽RP-18柱（150mM×2.1mm，1.7μm）的等物流系统中，在乙腈和0.1％甲酸中通过乙腈和0.1％甲酸组成的流动相，实现分析物的分离。使用电喷雾电离（ESI）离子源检测4-HI和L-异氨酸，在正离子模式下使用多反应监测（MRM）。在148.19> 74.02和132.17> 69.04的M / Z值下发现4-Hi和L-异氨酸的产物离子转变的前体。根据生物分析方法的指导，所有验证参数结果都在可接受的范围内。该方法表现出1-5000ng ml〜（α1）的稳健和可再现的线性度范围，其回归系数为0.9999。通过使用Thoth Pro（版本：4.3）软件，成功地应用于口服施用4-Hi（10mg kg〜（α1））后的药代动力学参数的方法。在此，基于AIC和SBC值的双隔室模型用于评估4-Hi的药代动力学参数。还通过测量甘油三酯和总胆固醇的水平进行药效学研究，并显示出4-Hi的药代动力学和药效学数据彼此相关。

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