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Trifluridine (FTD) and tipiracil (TPI) hydrochloride tablets (TAS-102) were used for the treatment of patients with metastatic rectal cancer that was resistant to conventional chemotherapy drugs. In this study, a rapid and sensitive liquid chromatography-tandem mass spectrometry method was developed and fully validated for the simultaneous determination of TPI, FTD, and the metabolite 5-trifluoromethyluracil (FTY) of FTD in human plasma. The plasma samples were prepared by protein precipitation. The chromatography separation was performed using ACE Excel 3 AQ (100 × 2.1 mm i.d., 1.7 µm, ACE, England) column protected by a security guard cartridge (4.0 × 2.0 mm i.d., 5 µm, Phenomenex, USA) with a gradient elution of 0.05% acetic acid in water and methanol at a flow rate of 0.35 mL/min. The MS/MS analysis was performed by using multiple reaction monitoring with the segmented polarity (positive for TPI: m/z 243.1→183.0, and negative for FTD: m/z 295.1→252.0 and FTY: m/z 178.9→158.9) electrospray ionization mode. The segmented polarity mode was designed to achieve two advantages: better sensitivity and simultaneous determination of the analytes with different ion polarities. The calibration ranges were as follows: 1.00–250 ng/ for TPI, 8.00–8000 ng/mL for FTD and 5.00–1250 ng/mL for FTY. The selectivity, accuracy, precision, matrix effect, recovery, carryover, dilution integrity and stability test results meet ICH acceptance criteria. The method was evaluated using the RGB model and successfully applied to a clinical study in patients with solid tumors. For TPI, FTD and FTY, the maximum plasma concentration was 137–147 ng/mL, 6160–6240 ng/mL and 724–725 ng/mL, respectively; the plasma elimination half-life was 1.69–1.78 h, 1.70 h, and 3.09–3.14 h, respectively, after an oral administration of 60 mg TAS-102. [Display omitted] • A sensitive LC-MS/MS method was established for pharmacokinetics of nucleoside drugs. • Simultaneous determination of tipiracil, trifluridine and 5-trifluoromethyluracil. • MS response of analytes can be improved by using segmented polarity. • The PK parameters were obtained in Chinese patients after the administration. [ABSTRACT FROM AUTHOR]