The effect of naringenin on the pharmacokinetics of ibrutinib in rat: a drug-drug interactions study.

The aim of this study was to investigate the effect of naringenin on the pharmacokinetics of ibrutinib in rats. A simple and sensitive quantitation method based on ultra-high performance liquid chromatography-Q-Exactive Orbitrap tandem mass spectrometry was developed and validated for t determination of ibrutinib in rat plasma. The samples were extracted using ethyl acetate containing 1% triethylamine and the separated on a Waters ACQUITY UPLC BEH C18 column with acetonitrile and water containing 0.1% formic acid as mobile phase. The assay showed good linearity over the concentration range of 1-1000 ng/mL with coefficient of correlation more than 0.995. The LLOQ was 1 ng/mL. The assay showed acceptable precision (RSD% < 8.65%), accuracy (RE% within ±15), extraction recovery (>78.25%) and negligible matrix effects. The validated method has been successfully applied to the pharmacokinetic study of ibrutinib in rats after oral administration of ibrutinib with or without coadministration of naringenin. Our results demonstrated that naringenin could significantly affect the pharmacokinetics of ibrutinib, including prolong its T1/2 , increase its AUC and reduce its CL. This study indicated that there was a potential for drug-drug interactions between naringenin and ibrutinib and coadministration of ibrutinib with naringenin or naringenin-containing herb medicines should be avoided in clinic.