科研之友
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摘要
Ibrutinib is a first-in-class, potent, orally administered, covalent inhibitor of Bruton's tyrosine kinase (BTK) that has been approved in the EU and USA for the treatment of patients with relapsed/refractory mantle cell lymphoma (MCL) or chronic lymphocytic leukaemia (CLL) and CLL patients with del 17p or TP53 mutation. In this work, a sensitive and selective ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for determination of ibrutinib in rat plasma was developed and validated. After addition of diazepam as an internal standard (IS), protein precipitation by methanol was used to prepare samples. Chromatographic separation was achieved on a UPLC BEH C18 column (2.1 mm x 100 mm, 1.7 mu m) with 0.1% formic acid and methanol as the mobile phase with gradient elution. An electrospray ionization source was applied and operated in positive ion mode; multiple reactions monitoring (MRM) mode was used for quantification using target fragment ions m/z 441.1 -> 138.0 for ibrutinib, and m/z 285.1 -> 193.1 for IS. Calibration plots were linear throughout the range 2-2000 ng/mL for ibrutinib in rat plasma. Mean recoveries of ibrutinib in rat plasma ranged from 88.1% to 90.8%. RSD of intra-day and inter-day precision were both < 7%. The accuracy of the method was between 95.0% and 105.6%. The method was successfully applied to pharmacokinetic study of ibrutinib after oral and intravenous administration. The bioavailability of ibrutinib was reported as 11.0%.
