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

PeerJ. 2023 Dec 8:11:e16601. doi: 10.7717/peerj.16601. eCollection 2023.

Abstract

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 CLz/F. The Cmax of oxycodone increased significantly upon co-administration of apatinib. In vitro, the Km 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 (IC50 = 3.29 ± 0.090 μM and 0.95 ± 0.88 μM, respectively) and a competitive and mixed mechanism in HLM (IC50 = 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.

Keywords: Apatinib; Icotinib; Interaction; Oxycodone; UPLC-MS/MS.

MeSH terms

  • Animals
  • Chromatography, High Pressure Liquid / methods
  • Chromatography, Liquid
  • Humans
  • Male
  • Oxycodone* / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Tandem Mass Spectrometry* / methods

Substances

  • apatinib
  • icotinib
  • Oxycodone

Grants and funding

This work was supported by the National Key Research and Development Program of China (2020YFC2008301), the National Natural Science Foundation of China (81973397), the Natural Science Foundation of Zhejiang Province (LTGC23H310001) and the project of the Wenzhou Municipal Science and Technology Bureau (Y20220192). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.