Determination and pharmacokinetic study of AZD-3759 in rat plasma by ultra performance liquid chromatography with triple quadrupole mass spectrometer

Abstract

Background: AZD-3759 is a new, potent, oral, active central nervous system-penetrant EGFR inhibitor. Despite promising clinical activity among patients pretreated and never treated with EGFR-tyrosine kinase inhibitors, no time saving pharmacokinetic study method has been reported in an animal model. Methods: Protein was precipitated with acetonitrile and then used for sample pre-processing. A CORTECS BEH C18 column was used to separate the analytes at 40°C. Acetonitrile and water (containing 0.1% formic acid) were chosen as the mobile phase at a flow rate of 0.4 mL/min. The analytes were quantified by multiple reaction monitoring mode with positive electrospray ionization. Results: The target fragment ions were m/z 460.38→141 for AZD-3759 and m/z 285.1→193.1 for internal standard diazepam. The calibration curve exhibited good linearity for AZD-3759 at a range of 1–500 ng/mL. The intra-run and inter-run precision variations were both < 8.22%. The recovery rate of AZD-3759 from plasma was > 76.4%. Conclusion: An accurate, simple ultra performance liquid chromatography with triple quadrupole mass spectrometer method was developed and validated to determine AZD-3759 in rat plasma. Our validated method can be applied to the pharmacokinetic study of AZD-3759 at an oral dosage of 10 mg/kg.