The effect of icotinib or apatinib on the pharmacokinetic profile of oxycodone in rats and the underlying mechanism.

This study aimed to investigate the interactions between icotinib/apatinib and oxycodone in rats and to unveil the underlying mechanism. An ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to determine oxycodone and its demethylated metabolite simultaneously. In vivo, Sprague-Dawley (SD) male rats were administered oxycodone with or without icotinib or apatinib. Blood samples were collected and subjected to UPLC-MS/MS analysis. An enzyme incubation assay was performed to investigate the mechanism of drug-drug interaction using both rat and human liver microsomes (RLM and HLM). The results showed that icotinib markedly increased the AUC((0-t)) and AUC((0-∞)) of oxycodone but decreased the CL(z/F). The C(max) of oxycodone increased significantly upon co-administration of apatinib. In vitro, the K(m) value of oxycodone metabolism was 101.7 ± 5.40 μM and 529.6 ± 19.60 μM in RLMs and HLMs, respectively. Icotinib and apatinib inhibited the disposition of oxycodone, with a mixed mechanism in RLM (IC(50) = 3.29 ± 0.090 μM and 0.95 ± 0.88 μM, respectively) and a competitive and mixed mechanism in HLM (IC(50) = 22.34 ± 0.81 μM and 0.48 ± 0.05 μM, respectively). In conclusion, both icotinib and apatinib inhibit the metabolism of oxycodone in vitro and in vivo. Therefore, the dose of oxycodone should be reconsidered when co-administered with icotinib or apatinib.