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Foretinib衍生物LWK-126在不同种属肝微粒体中的代谢稳定性研究
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| 篇名： | Foretinib衍生物LWK-126在不同种属肝微粒体中的代谢稳定性研究 |
| TITLE： | Study on Metabolic Stability of Foretinib Derivative LWK- 126 in Liver Microsomes of Different Species |
| 摘要： | 目的：建立测定肝微粒体中Foretinib衍生物LWK-126质量浓度的方法，研究其在大鼠、比格犬、人肝微粒体中的代谢稳定性。方法：采用体外肝微粒体孵育体系，将LWK-126分别溶于由还原型烟酰胺腺嘌呤二核苷酸磷酸溶液启动的大鼠、比格犬、人肝微粒体孵育体系中，于37℃水浴下分别孵育0、5、10、20、30、60min时加入含内标（1μg/mL甲苯磺丁脲）的乙腈终止反应，并采用超高效液相色谱-串联质谱法检测各孵育体系中LWK-126的质量浓度。以WatersBEHC18为色谱柱，以水（含0.01％甲酸）-乙腈（含0.01％甲酸）为流动相进行梯度洗脱，流速为0.4mL/min，柱温为30℃，进样量为2μL；离子源为电喷雾电离源，采用正离子模式采集，扫描范围为m/z50→1200。以孵育0min时LWK-126的质量浓度为参照，计算其在不同孵育体系中的剩余百分率与酶动力学参数。结果：LWK-126检测质量浓度的线性范围为0.05～15μg/mL（R2＝0.9992），定量下限为0.05μg/mL，最低检测限为0.01μg/mL，精密度、准确度、提取回收率和基质效应均符合生物样品定量分析的要求。LWK-126在人、大鼠、比格犬肝微粒体中孵育60min后的剩余百分率分别为（33.17±4.52）％、（3.14±6.73）％、（1.38±5.85）％，半衰期分别为33.15、11.76、5.62min，清除率分别为38.45、118.81、245.76μL（/min·mg）。结论：成功建立了肝微粒体中LWK-126质量浓度的测定方法。LWK-126在不同种属肝微粒体中的代谢稳定性排序依次为人＞大鼠＞比格犬。 |
| ABSTRACT： | OBJECTIVE：To establish the metho d for the concentration det ermination of foretinib derivative LWK- 126 in liver microsomes，and to study its metabolism stability in liver microsomes of rats ，Beagle dogs and human. METHODS ：In the in vitro incubation system of liver microsomes ，LWK-126 was dissolved in liver microsomal incubation systems of rats ，Beagle dog and human initiated by reduced nicotinamide adenine dinucleotide phosphate solution. After incubation in water at 37 ℃ for 0，5，10，20， 30 and 60 min，the reaction was terminated with acetonitrile containing internal standard （1 μg/mL tolbutamide）. UPLC-MS/MS method was applied to determine the concentration of LWK- 126 in the incubation systems. The determination was performed on Waters BEH C 18 column with mobile phase consisted of water （containing 0.1％ formic acid ）-acetonitrile（containing 0.1％ formic acid）by gradient elution at the flow rate of 0.4 mL/min. The column temperature was 30 ℃，and the sample size was 2 μL. The mass spectral analysis was performed in a positive electrospray ionization mode ，and the full MS experiment was run with the selective reaction monitoring mode with a scanning range of m/z 50→1 200. Taking the concentration of LWK- 126 at 0 min as reference，the remaining percentage and the enzyme kinetic parameters were calculated. RESULTS ：The linear range of LWK- 126 was 0.05-15 μg/mL（R 2＝0.999 2）；the lower limit of quantification was 0.05 μg/mL，and the lowest detection limit was 0.01 μg/mL. The precision，accuracy，extraction recovery and matrix effect all met the analysis requirements of biological samples. The remaining percentage of LWK- 126 in liver microsomes of human ，rats and Beagle dogs for 60 min were （33.17±4.52）％，（3.14± 6.73）％，（1.38±5.85）％；t1/2 of them were 33.15，11.76，5.62 min；the clearance rates were 38.45，118.81，245.76 μL（/ min·mg）， respectively. CONCLUSIONS ：The method for the content ； determination of LWK- 126 in liver microsomes is established successfully. The order of metabolic stability of LWK- 126 in 〔2016〕4015） liver microsomes of different species is human ＞rats＞Beagle dogs. |
| 期刊： | 2021年第32卷第11期 |
| 作者： | 王忠元，杨华丽，崔杏，朱高峰，汤磊，廖伟科 |
| AUTHORS： | WANG Zhongyuan，YANG Huali，CUI Xing，ZHU Gaofeng，TANG Lei，LIAO Weike |
| 关键字： | LWK-126；超高效液相色谱-串联质谱法；肝微粒体；代谢稳定性 |
| KEYWORDS： | LWK-126；UPLC-MS/MS；Liver microsomes ； |
| 阅读数： | 264 次 |
| 本月下载数： | 10 次 |
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