Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia; Bioavailability Laboratory, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia; Bioavailability Laboratory, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
J Pharm Biomed Anal. 2019 Mar 20;166:244-251. doi: 10.1016/j.jpba.2019.01.023. Epub 2019 Jan 14.
Motesanib is a potent angiokinase inhibitor, has shown potential therapeutic effects against various cancers. An accurate, reproducible, rapid, specific, sensitive, and valid ultraperformance liquid chromatography-tandem mass spectrometry method was established to quantify motesanib in rat plasma. Motesanib and linifanib (used as an internal standard; IS) were extracted from plasma by liquid-liquid extraction using tert-butyl methyl ether as extracting agent. Chromatographic separation was performed on Acquity™ UPLC BEH™ C column (100 mm × 2.1 mm i.d., 1.7 μm; Waters Corp., USA) using a mobile phase comprising of 0.1% formic acid acetonitrile: ammonium acetate (90:10 v/v) eluted at a flow rate of 0.25 mL/min. The electrospray ionization in the positive-mode was used for sample ionization. In the multiple reaction monitoring mode, motesanib and the IS were quantified using precursor-to-product ion transitions of m/z 374.03 → 212.02 and m/z 376.05 → 251.05, respectively. The ranges of the calibration curves were 5.0-1000.0 ng/mL with coefficient of determination of ≥0.998. The method was validated by following recently implemented USFDA guideline for bioanalytical method validation. The lower limit of quantification was 5.0 ng/mL, whereas the intra-day and inter-day accuracies of quality controls (QCs) samples were ranged between 88.91% to 95.65% and 90.20% to 102.17%, respectively. In addition, the linearity, recovery, precision, and stability parameters were found to be within the acceptable range. The method was applied successfully to in vitro microsomal metabolic stability and preliminary oral pharmacokinetic studies in rats. The applied UPLC/MS/MS method was found to be adequately sensitive and therefore suitable for application in routine motesanib pharmacokinetic studies.
莫特塞尼布是一种有效的血管激酶抑制剂，已显示出对多种癌症的潜在治疗效果。建立了一种准确、重现、快速、特异、灵敏和有效的超高效液相色谱-串联质谱法，用于定量检测大鼠血浆中的莫特塞尼布。莫特塞尼布和利尼法尼（作为内标；IS）用叔丁基甲基醚作为提取剂通过液液萃取从血浆中提取。采用 Acquity™ UPLC BEH™ C 柱（100mm×2.1mm i.d.，1.7μm；Waters 公司，美国）进行色谱分离，流动相为 0.1%甲酸乙腈：乙酸铵（90:10v/v），流速为 0.25mL/min。采用电喷雾正离子化模式进行样品离子化。在多重反应监测模式下，莫特塞尼布和 IS 的定量分析采用 m/z 374.03→212.02 和 m/z 376.05→251.05 的前体到产物离子跃迁。校准曲线的范围为 5.0-1000.0ng/mL，相关系数≥0.998。该方法按照美国 FDA 最近实施的生物分析方法验证指南进行了验证。定量下限为 5.0ng/mL，而 QC 样品的日内和日间准确度范围分别为 88.91%-95.65%和 90.20%-102.17%。此外，线性、回收率、精密度和稳定性参数均在可接受范围内。该方法成功应用于体外微粒体代谢稳定性和大鼠初步口服药代动力学研究。应用的 UPLC/MS/MS 方法具有足够的灵敏度，因此适合用于常规莫特塞尼布药代动力学研究。
