Both entecavir and crizotinib are substrates of organic cation transporter 2 (OCT2). The aim of present study was to investigate the mechanisms of drug interactions between these two drugs. Kinetic analysis of entecavir on crizotinib uptake was conduct. Plasma concentration of crizotinib in rats and lung cancer patients, uptake of crizotinib in kidney slices and OCT2 transfected cells, were determined by LC-MS/MS. The clinical pharmacokinetic interactions and impact on adverse reaction of crizotinib in lung cancer patients were investigated. Steady-state through concentration of crizotinib was measured. The crizotinib-related adverse reactions were recorded in lung cancer patients with and without entecavir. Entecavir and 1-methyl-4-phenylpyridinium iodide significantly inhibited the uptake of crizotinib in kidney slices. Kinetic constants for crizotinib uptake by OCT2 were Km 1.16 ± 0.26 µM, Vmax 12.05 ± 0.53 µmol/min mg-1 protein and Ki 9.711 nM. Entecavir can inhibit crizotinib transport by OCT2 in kidney. Co-administration of entecavir significantly reduced the elimination of crizotinib in rats. In lung cancer patients, the steady-state AUCss of crizotinib increased approximately 1.2 fold (p < 0.05) but clearance was decreased by approximately 15% in the presence of entecavir. Steady-state through concentration of crizotinib significantly increased 1.3-fold when co-administrated with entecavir (p>0.001). Co-medication of entecavir significantly (p < 0.05) increased the risks of vision disorders, diarrhea and vomiting 1.6-, 2.3- and 1.8-fold. Entecavir could increase the exposure and reduce the elimination of crizotinib in lung cancer patients. Moreover, the presence of entecavir could significantly increase the incidences of adverse reaction of crizotinib.
Animals Biological Transport