UPLC-MS/MS 技术研究伊曲康唑和伏立康唑对贝格尔犬 ripretinib 的药代动力学影响。
The Pharmacokinetic Effect of Itraconazole and Voriconazole on Ripretinib in Beagle Dogs by UPLC-MS/MS Technique.
机构信息
Department of Pharmacy, School of Basic Medical Sciences, Henan University of Science and Technology, Luoyang, 471023, People's Republic of China.
Functional Experiment Teaching Center, School of Basic Medical Sciences, Henan University of Science and Technology, Luoyang, 471023, People's Republic of China.
出版信息
Drug Des Devel Ther. 2021 Nov 30;15:4865-4873. doi: 10.2147/DDDT.S337864. eCollection 2021.
BACKGROUND
A new UPLC-MS/MS technique for the determination of ripretinib in beagle dog plasma was developed, and the pharmacokinetic effects of voriconazole and itraconazole on ripretinib in beagle dogs were studied.
METHODS
After extraction with ethyl acetate under alkaline conditions, ripretinib was detected using avapritinib as the internal standard (IS). The mobile phases were 0.1% formic acid-acetonitrile. The scanning method was multi-reaction monitoring using ESI+ source, and the ion pairs for ripretinib and IS were m/z 509.93→416.85 and 499.1→482.09, respectively. This animal experiment adopted a three period self-control experimental design. In the first period, ripretinib was orally administered to six beagle dogs at a dose of 5 mg/kg. In the second period, the same six beagle dogs were orally given itraconazole at a dose of 7 mg/kg, after 30 min, ripretinib was orally given. In the third period, voriconazole at a dose of 7 mg/kg was given orally, and then ripretinib was orally given. At different time points, the blood samples were collected. The concentration of ripretinib was detected, and the pharmacokinetic parameters of ripretinib were calculated.
RESULTS
Ripretinib had a good linear relationship in the range of 1-1000 ng/mL. The precision, accuracy, recovery, matrix effect and stability met the requirements of the guiding principles. After erdafitinib combined with itraconazole, the C and AUC of ripretinib increased by 38.35% and 36.36%, respectively, and the t was prolonged to 7.53 h. After ripretinib combined with voriconazole, the C and AUC of ripretinib increased by 37.44% and 25.52%, respectively, and the t was prolonged to 7.33 h.
CONCLUSION
A new and reliable UPLC-MS/MS technique was fully optimized and developed to detect the concentration of ripretinib in beagle dog plasma. Itraconazole and voriconazole could inhibit the metabolism of ripretinib in beagle dogs and increase the plasma exposure of ripretinib.
背景
建立了一种新的 UPLC-MS/MS 法测定比卡替尼在比格犬血浆中的浓度，并研究了伏立康唑和伊曲康唑对比格犬比卡替尼的药代动力学影响。
方法
采用碱性条件下乙酸乙酯提取，以阿伐替尼为内标（IS），采用 0.1%甲酸-乙腈为流动相，电喷雾离子源（ESI+）多反应监测扫描方式，比卡替尼和 IS 的离子对分别为 m/z509.93→416.85 和 499.1→482.09。该动物实验采用三周期自身对照设计。第一周期，6 只比格犬单次口服 5 mg/kg 比卡替尼；第二周期，同一 6 只比格犬 30 min 后口服 7 mg/kg 伊曲康唑，再口服 5 mg/kg 比卡替尼；第三周期，6 只比格犬口服 7 mg/kg 伏立康唑，再口服 5 mg/kg 比卡替尼。于不同时间点采集血样，检测比卡替尼浓度，计算比卡替尼的药代动力学参数。
结果
比卡替尼在 1~1000 ng/mL 范围内线性关系良好。精密度、准确度、回收率、基质效应和稳定性均符合指导原则的要求。与伊曲康唑合用后，比卡替尼的 C 和 AUC 分别增加了 38.35%和 36.36%，t 延长至 7.53 h。与伏立康唑合用后，比卡替尼的 C 和 AUC 分别增加了 37.44%和 25.52%，t 延长至 7.33 h。
结论
建立并充分优化了一种新的可靠的 UPLC-MS/MS 法，用于检测比格犬血浆中比卡替尼的浓度。伊曲康唑和伏立康唑可抑制比格犬比卡替尼的代谢，增加比卡替尼的血浆暴露量。
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