小分子抗肿瘤药物SPH0396在大鼠体内的药代动力学

Pharmacokinetics study of an anti-tumor candidate SPH0396 in rats

目的 ：建立定量测定大鼠血浆中抗肿瘤药a SPH0396的LC-MS/MS方法,并将其应用于大鼠体内药代动力学研究。方法 ：血浆样品在Waters BEH C18柱上以0.1%甲酸水溶液-0.1%甲酸乙腈溶液进行梯度洗脱;采用MRM方式进行定量测定,监测离子对为m/z 553.4→453.4（SPH0396）和m/z 533.3→259.9（内标ponatinib）。结果 ：SPH0396在1.11~2 488.50 ng/ml的浓度范围内呈良好的线性关系（R2=0.999）,定量下限为1.11 ng/ml,回收率和精密度均符合生物样品检测要求。大鼠静注3 mg/kg SPH0396后,t1/2为3.43±0.37 h,CL为2.13±0.21L/h·kg,Vdss为6.76±0.26 L/kg。大鼠口服5、15和50 mg/kg的SPH0396后吸收较慢,Tmax为4~6 h。大鼠口服不同剂量的SPH0396,Cmax和AUC（0-t）的增加比例均高于剂量增加比例,生物利用度分别为17.15%、25.58%和36.19%。结论：本研究首次建立了特异、灵敏、便捷的定量检测大鼠血浆中SPH0396的LC-MS/MS方法,并成功应用于SPH0396的大鼠药代动力学研究。

Objective： To develop and validate an LC-MS/MS method for the quantitative analysis of a new antitumor candidate SPH0396 in rat plasma so as to be applied to the pharmacokinetic study in rats. Methods： The chromatographic separation of SPH0396 was performed on BEH C18 column by a gradient elution with water containing 0.1% formic acid and acetonitrile containing 0.1% formic acid. The MS detection was conducted on MRM mode and the ion-pairs monitored were m/z 553.4 → 453.4（SPH0396） and m/z 533.3 → 259.9 with ponatinib as an internal standard. Results： A standard curve for the determination of SPH0396 showed a good linearity over the range of 1.11 ~ 2 488.50 ng/ml（R2=0.999） with the lower limit of quantification at 1.11 ng/ml. The recovery and precision could meet the requirement of bioanalysis. After intravenous administration of SPH0396, the t1/2, CL and Vdss in rats were 3.43±0.37 h, 2.13±0.21 L/h·kg and 6.76±0.26 L/kg, respectively. The absorption of SPH0396 in rats was slow after oral administration. The peak level was reached at 4 ~ 6 h. The oral bioavailability was 17.15%, 25.58% and 36.19% at different doses, respectively. Conclusion： The LC-MS/MS method is specific, sensitive, rapid and simple and is suitable for pharmacokinetic study of SPH0396 in rats.