Application of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to the pharmacokinetics, tissue distribution and excretion studies of felotaxel (SHR110008) in tumor-bearing mice.
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.
Department of Pharmacy, Xijing Hospital of the Fourth Military Medical University, 17 Changlexi Street, Xi'an 710032, Shanxi, China.
Yi
Y
Ding
ChengTao
C
Lu
Jing
J
Yang
Xin
X
Jin
Lin
L
Yang
Chao
C
Wang
ZongYing
Z
Ma
YanRong
Y
Zhu
LiKun
L
Ding
YanYan
Y
Jia
AiDong
A
Wen
D000818:Animals; D000970:Antineoplastic Agents / Q000032:analysis / Q000737:chemistry / Q000493:pharmacokinetics*; D002853:Chromatography, Liquid / Q000379:methods*; D003975:Diazepam; D004355:Drug Stability; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D053719:Tandem Mass Spectrometry / Q000379:methods*; D043823:Taxoids / Q000032:analysis / Q000737:chemistry / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D043823:Taxoids; C571875:felotaxel; D003975:Diazepam