Development and validation of UPLC-MS/MS method for the simultaneous quantification of anaplastic lymphoma kinase inhibitors, alectinib, ceritinib, and crizotinib in Wistar rat plasma with application to bromelain-induced pharmacokinetic interaction

Abstract

Bromelain, the aqueous extract of pineapple, has been used as a food supplement with reported nutritional and therapeutic benefits. Bromelain has anti-cancer, anti-inflammatory, antithrombotic, and fibrinolytic effects. Anaplastic lymphoma kinase (ALK) inhibitors, including alectinib (ALC), ceritinib (CER), and crizotinib (CRZ), have been efficiently used in the management of non-small cell lung cancer (NSCLC). The solubility of ALC, CER, and CRZ is much higher at low acidic pH (pH 1) and it decreases as the pH increases affecting their absorption with a subsequent decrease in their bioavailability. It was thought that the intake of bromelain could result in a decrease in the bioavailability of ALC, CER, and CRZ due to bromelain-induced alkalizing effect following digestion. On the contrary, bromelain could possibly increase plasma exposure of the cited drugs due to its known muco-permeation enhancing effect. The therapeutic-anticancer effect of bromelain can be possibly increased/enhanced with concomitant intake of other anticancer medications or it can add to the value of food supplements for its known nutritional benefits. Thus, this work aims at studying the possibility of any PK interaction when bromelain was taken while on ALC/CER/CRZ therapy. In this work, a new UPLC-MS/MS method was developed and validated for the simultaneous determination of ALC, CER, and CRZ in rat plasma. Further application of the proposed method was performed to test the possibility of the PK interaction between bromelain and the selected ALK inhibitors in Wistar rats. Simple protein precipitation with acetonitrile was used for sample preparation. Chromatographic analysis was performed on Waters BEH™ C18 column with a mixture of acetonitrile/water containing 0.1 % formic acid (70: 30, v/v) as the mobile phase. The method permitted the analysis of ALC, CER, and CRZ in concentration ranges of 2-200, 0.4-200, and 4.0-200 ng/mL, respectively. Bromelain administration caused a significant decrease in plasma levels of CER and CRZ with lowered C_max, AUC_0-t and AUC_0-∞, along with an increase in the apparent clearance. However, no significant effect was noticed with ALC. Thus, attention should be paid to avoid the intake of bromelain with CER or CRZ.

Keywords: Alectinib; Bromelain; Ceritinib; Crizotinib; Pharmacokinetic interaction; Rat plasma.