Comparative pharmacokinetic profiles of selected irreversible tyrosine kinase inhibitors, neratinib and pelitinib, with apigenin in rat plasma by UPLC-MS/MS

Journal Article

2017

Abahussain, Hadir M. Maher, Nourah Z. Alzoman, Shereen M. Shehata, Ashwag O. . 2017

tNeratinib (NER) and pelitinib (PEL) are irreversible tyrosine kinase inhibitors (TKIs) that have beenrecently employed in cancer treatment. Apigenin (API), among other flavonoids, is known to haveantioxidant, anti-proliferative, and carcinogenic effect. API can potentiate the antitumor effect ofchemotherapeutic agents and/or alleviate the side effects of many anticancer agents. Since TKIs aremostly metabolized by CYP3A4 enzymes and that API could alter the enzymatic activity, potential druginteractions could be expected following their co-aministration. In the present study, a bioanalyticalUPLC–MS/MS method has been developed and validated for the quantification of NER and PEL in ratplasma, using domperidone (DOM) as an internal standard. Sample preparation was carried out usingsolid phase extraction (SPE) with C18 cartridges with good extraction recovery of not less than 92.42%(NER) and 89.73% (PEL). Chromatographic analysis was performed on a Waters BEH C18 column with amobile phase composed of acetonitrile and water, (70:30, v/v), each with 0.1% formic acid. Quantitationwas performed using multiple reaction monitoring (MRM) of the transitions from protonated precursorions [M+H]+, at m/z 557.30 (NER), m/z 468.21 (PEL), and at m/z 426.27 (DOM), to selected product ions atm/z 112.05 (NER), m/z 395.22 (PEL), and at m/z 175.18 (DOM). The method was fully validated as per theFDA guidelines over the concentration range of 0.5–200 ng/mL with very low lower limit of quantification(LLOQ) of 0.5 ng/mL for both NER and PEL. The intra- and inter-day assay precision and accuracy wereevaluated for both drugs and the calculated values of percentage relative standards deviations (%RSD)and relative errors (%Er) were within the acceptable limits (<15%) for concentrations other than LLOQ and20% for LLOQ. The applicability of the method was extended to study the possibility of drug interactionsfollowing the oral co-administration of NER/PEL with API. Thus, this study could be readily applied intherapeutic drug monitoring (TDM) of cancerous patients receiving such drug combinations.

• Volume Number: 137
• Magazine \ Newspaper: Journal of Pharmaceutical and Biomedical Analysis
• Pages: 258–267