[Simultaneous determination of donafenib and its N-oxide metabolite in human plasma by liquid chromatography-tandem mass spectrometry].

Abstract

Donafenib is the deuterium derivative of sorafenib, and is an anti-tumor drug in clinical trials. An accurate and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous determination of donafenib and its N-oxide metabolite in human plasma. The analytes and internal standards (sorafenib and sorafenib N-oxide) were extracted from plasma by protein precipitation with acetonitrile, and separated on a Gemini C18 (50 mm × 2.0 mm, 5 μm) column using a gradient elution procedure. The mobile phase consisted of acetonitrile and 5 mmol ·L−1 ammonium acetate (0.2% formic acid) at a flow rate of 0.7 mL·min−1. The total run time was 5.0 min. Positive electrospray ionization was performed using multiple reaction monitoring (MRM) with transitions of m/z 468.2 → 273.2 for donafenib and m/z 465.2 → 270.2 for its internal standard sorafenib, m/z 484.2 → 289.2 for donafenib N-oxide and m/z 481.2 → 286.2 for its internal standard sorafenib N-oxide. The standard curves were linear in the range of 5.00−5 000 ng·mL−1 for donafenib, and 1.00−1 000 ng·mL−1 for donafenib N-oxide. The method was validated and successfully applied to the pharmacokinetics study of donafenib tosylate tablets in volunteers.