Determination of Puquitinib in Human Plasma by HPLC-ESI MS/MS: Application to Pharmacokinetic Study

摘要

Background and ObjectivePuquitinib mesylate (XC-302) is a new multiple-target anticancer inhibitor, which directly suppresses the activity of phosphatidylinositol 3-kinase (PI3K). This study was aimed to develop a sensitive and specific liquid chromatography electrospray ionization tandemmass spectrometry (HPLC-ESI MS/MS) method for the quantification and pharmacokinetic investigation of plasma puquitinib in cancer patients.MethodsThe analytes of human plasma were prepared by liquid-liquid extraction using methyl-t-butyl ether (MTBE). The plasma analytes were separated by HPLC on Thermo ODS Hypersil column (2.1x150mm; 3m) at 25 degrees C with 5mmol/L ammonium acetate (A)-acetonitrile (B) (30:70, v/v) as the mobile phase.ResultsThe total run time was 3.5min and the elution of puquitinib was at 1.38min. The detection were analyzed by multiple reaction monitoring (MRM) mode with positive-ion electrospray ionization (ESI) interface using the respective [M+H](+) ions: m/z 318.2261.1 for puquitinib and m/z 258.2121.0 for the internal standard (etofesalamide). The optimized method provided a good linear relation over the concentration range of 1.00-500.00ng/mL (r=0.9944) for puquitinib. The intra-day and inter-day precision (relativestandard deviation [RSD%]) were within 9.83%, and the intra-day and inter-day accuracy ranged from 91.05 to 103.26%. The lower limit of quantitation (LLOQ) was 1.00ng/mL. The absolute extraction recovery was on an average of 50.43% for puquitinib and 49.3% for internal standard. In addition, the maximum plasma concentration (C-max)of puquitinib in dosage from 50 to 800mg/m(2) in the human study showed an increased linearly (57.1-1289.2ng/mL), which displayed that the concentrations had reached effective levels.ConclusionsThe optimized method was successfully applied to the pharmacokinetic profile study in human cancer patient plasma after the oral administration of puquitinib.