Dittakavi Sreekanth, Jat Rakesh Kumar, Mallurwar Sadanand Rangnathrao, Jairam Ravi Kumar, Mullangi Ramesh
Drug Metabolism and Pharmacokinetics, Jubilant Biosys, Industrial Suburb, Yeshwanthpur, Bangalore-560 022, India.
Institute of Pharmacy, Shri Jagdish Prasad Jhabarmal Tibrewala University, Jhunjhunu-Churu Road, Chudela, Jhunjhunu-333001, Rajasthan.
ADMET DMPK. 2019 Mar 5;7(2):131-139. doi: 10.5599/admet.648. eCollection 2019.
A simple, selective and rapid LC-ESI-MS/MS method has been developed and validated for the quantification of ivosidenib in mice plasma using warfarin as an internal standard (I.S.) as per regulatory guideline. Sample preparation was accomplished through a simple protein precipitation process. Chromatography of ivosidenib and the I.S. was achieved on an Atlantis dC column using an isocratic mobile phase comprising 0.2 % formic acid in water and acetonitrile (25:75, v/v) delivered at a flow rate of 1.0 mL/min. LC-MS/MS was operated under the multiple reaction-monitoring mode (MRM) using the electrospray ionization technique in positive ion mode and the transitions of m/z 583.1→186.1 and m/z 309.2→251.3 were used to quantitate ivosidenib and the I.S, respectively. The total chromatographic run time was 2.0 min. Linearity was established in the concentration range of 1.10-3293 ng/mL (r>0.99). The intra- and inter-day accuracy and precision for ivosidenib in mice plasma were in the range of 5.72-9.91 and 5.90-10.7 %, respectively. Ivosidenib was found to be stable on bench-top for 6 h, up to three freeze-thaw cycles, in in-injector for 24 h and for one month at -80 °C. The applicability of the validated method has been demonstrated in a mice pharmacokinetic study. Following intravenous (2 mg/kg) and oral (5 mg/kg) administration of ivosidenib to mice, concentrations were quantifiable up to 24 and 48 h, respectively. The bioavailability was 61 %.
已开发并验证了一种简单、选择性且快速的液相色谱-电喷雾串联质谱（LC-ESI-MS/MS）方法，用于按照监管指南以华法林作为内标物（I.S.）对小鼠血浆中的艾伏尼布进行定量分析。样品制备通过简单的蛋白沉淀过程完成。艾伏尼布和内标物的色谱分离在Atlantis dC柱上进行，使用等度流动相，该流动相由含0.2%甲酸的水溶液和乙腈（25:75，v/v）组成，流速为1.0 mL/min。LC-MS/MS在多反应监测模式（MRM）下运行，采用电喷雾电离技术的正离子模式，分别使用m/z 583.1→186.1和m/z 309.2→251.3的跃迁来定量艾伏尼布和内标物。总色谱运行时间为2.0分钟。在1.10 - 3293 ng/mL的浓度范围内建立了线性关系（r>0.99）。小鼠血浆中艾伏尼布的日内和日间准确度及精密度分别在5.72 - 9.91%和5.90 - 10.7%的范围内。发现艾伏尼布在台式上6小时内稳定，最多可进行三个冻融循环，在进样器中24小时内稳定，在-80°C下可稳定保存一个月。已在小鼠药代动力学研究中证明了该验证方法的适用性。给小鼠静脉注射（2 mg/kg）和口服（5 mg/kg）艾伏尼布后，浓度分别在24小时和48小时内可定量。生物利用度为61%。
