Department of Pharmacy, Xijing Hospital of the Fourth Military Medical University, 17 Changlexi Street, Xi'an 710032, Shanxi, China.
J Chromatogr B Analyt Technol Biomed Life Sci. 2012 Mar 1;887-888:61-6. doi: 10.1016/j.jchromb.2012.01.010. Epub 2012 Jan 23.
Felotaxel (SHR110008), currently under clinical investigation in phase I trial, is a new effective taxane with greater anticancer activity and less toxicity than docetaxel. Pharmacokinetic studies in animal models are the important components in clinical development of this agent. In this study, a rapid and sensitive analytical method based on high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been developed for the determination of felotaxel in tumor-bearing mice plasma, urine, feces and tissues (brain, heart, liver, lung and kidney and tumor). For all matrices, sample preparation involved liquid-liquid extraction with ethyl acetate. Calibration curves (1/x² weighted) offered satisfactory linearity (r² ≥ 0.995) within the test range. The lower limit of quantitation (LLOQ) for all matrices was 10 ng/ml except that for mouse plasma and brain LLOQ was 1 ng/ml. The accuracy and precision ranged from 86.1 to 107.2% and 1.1 to 9.2%, respectively. Recoveries (73.9-96.1%) and matrix effects (76.4-97.2%) were satisfactory in all the biological matrices examined. Stability studies (85.1-101.5%) showed that felotaxel was stable both during the assay procedure and long-term storage. The assay was successfully applied to plasma pharmacokinetics, tissue distribution and excretion study of mice. The pharmacokinetic parameters, such as half-life, mean residence time, maximum concentration were determined. The preclinical data are useful for the design of clinical trials of felotaxel.
福沙匹坦（SHR110008）是一种正在进行 I 期临床试验的新型紫杉烷类药物，其抗癌活性强于多西他赛，毒性小于多西他赛。在该药物的临床开发中，动物模型中的药代动力学研究是重要组成部分。在本研究中，建立了一种基于高效液相色谱-串联质谱（LC-MS/MS）的快速灵敏分析方法，用于测定荷瘤小鼠血浆、尿液、粪便和组织（脑、心、肝、肺、肾和肿瘤）中的福沙匹坦。对于所有基质，样品制备均采用乙酸乙酯进行液-液萃取。除了小鼠血浆和脑组织外，所有基质的定量下限（LLOQ）均为 10ng/ml，LLOQ 为 1ng/ml。在测试范围内，校准曲线（1/x² 加权）具有良好的线性（r²≥0.995）。准确度和精密度范围分别为 86.1%-107.2%和 1.1%-9.2%。在所考察的所有生物基质中，回收率（73.9%-96.1%）和基质效应（76.4%-97.2%）均令人满意。稳定性研究（85.1%-101.5%）表明，福沙匹坦在分析过程中和长期储存中均稳定。该方法成功应用于小鼠血浆药代动力学、组织分布和排泄研究。确定了福沙匹坦的药代动力学参数，如半衰期、平均停留时间、最大浓度等。这些临床前数据为福沙匹坦的临床试验设计提供了有用信息。
