Liu Jia, Liu Hanqing, Zeng Qingqi
Department of Pharmacy, Jiangsu Health Vocational College, Nanjing, China.
Department of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
Biomed Chromatogr. 2019 May;33(5):e4507. doi: 10.1002/bmc.4507. Epub 2019 Mar 6.
The aim of this study was to investigate the effect of naringenin on the pharmacokinetics of ibrutinib in rats. A simple and sensitive quantitation method based on ultra-high-performance liquid chromatography-Q-Exactive Orbitrap tandem mass spectrometry was developed and validated for the determination of ibrutinib in rat plasma. The samples were extracted using ethyl acetate containing 1% triethylamine and separated on a Waters Acquity UPLC BEH C column with acetonitrile and water containing 0.1% formic acid as mobile phase. The assay showed good linearity over the concentration range of 1-1000 ng/mL with coefficient of correlation >0.995. The LLOQ was 1 ng/mL. The assay showed acceptable precision (RSD < 8.65%), accuracy (RE within ±15%), extraction recovery (>78.25%) and negligible matrix effects. The validated method has been successfully applied to the pharmacokinetic study of ibrutinib in rats after oral administration of ibrutinib with or without coadministration of naringenin. Our results demonstrated that naringenin could significantly affect the pharmacokinetics of ibrutinib, including prolonging its half-life, increase the area under the concentration-time curve and reducing its clearance time. This study indicated that there is potential for drug-drug interactions between naringenin and ibrutinib, and coadministration of ibrutinib with naringenin or naringenin-containing herbal medicines should be avoided in the clinic.
本研究的目的是考察柚皮素对依鲁替尼在大鼠体内药代动力学的影响。建立了一种基于超高效液相色谱-Q-Exactive Orbitrap串联质谱的简单、灵敏的定量方法，并对其进行了验证，用于测定大鼠血浆中的依鲁替尼。样品用含1%三乙胺的乙酸乙酯萃取，在Waters Acquity UPLC BEH C柱上分离，以含0.1%甲酸的乙腈和水为流动相。该测定法在1-1000 ng/mL的浓度范围内显示出良好的线性，相关系数>0.995。最低定量限为1 ng/mL。该测定法显示出可接受的精密度（相对标准偏差<8.65%）、准确度（相对误差在±15%以内）、萃取回收率（>78.25%）和可忽略的基质效应。经过验证的方法已成功应用于依鲁替尼单独给药或与柚皮素联合给药后大鼠体内依鲁替尼的药代动力学研究。我们的结果表明，柚皮素可显著影响依鲁替尼的药代动力学，包括延长其半衰期、增加浓度-时间曲线下面积并缩短其清除时间。本研究表明柚皮素与依鲁替尼之间存在药物相互作用的可能性，临床应避免依鲁替尼与柚皮素或含柚皮素的草药联合使用。
