The effect of naringenin on the pharmacokinetics of ibrutinib in rat: A drug-drug interaction 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 the determination of ibrutinib in rat plasma. The samples were extracted using ethyl acetate containing 1% triethylamine and separated on a Waters Acquity UPLC BEH C-18 column with acetonitrile and water containing 0.1% formic acid as mobile phase. The assay showed good linearity over the concentration range of 1-1000ng/mL with coefficient of correlation >0.995. The LLOQ was 1ng/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 prolonging its half-life, increase the area under the concentration-time curve and reducing its clearance time. This study indicated that there is potential for drug-drug interactions between naringenin and ibrutinib, and coadministration of ibrutinib with naringenin or naringenin-containing herbal medicines should be avoided in the clinic.