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

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

Qi Zhou  1 , Feng Ye  1 , Zhize Ye  2 , Nanyong Gao  1 , Qihui Kong  1 , Xiaoqin Hu  1 , Jianchang Qian  1 , Bin Wu  3
Affiliations

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

Qi Zhou et al. PeerJ. .

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.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1. Representative chromatograms of oxycodone, noroxycodone and IS.
(A) The blank plasma sample; (B) the blank plasma sample spiked with oxycodone, noroxycodone and IS; (C) rat plasma sample after administration.
Figure 2
Figure 2. Michaelis constant (Km) in RLM (rat liver microsomes)/HLM (human liver microsomes) and comparison of the inhibitory effects of drugs on the metabolism of oxycodone in RLM.
(A) Km in RLM. (B) Km in HLM. The incubition assay was performed as indicated as in the method. (C) Comparison of the inhibitory effects of drugs on the metabolism of oxycodone in RLM. Data are presented as the means ± SD, n = 3.
Figure 3
Figure 3. Half-maximal inhibitory concentration (IC50) value in RLM/HLM.
(A) Apatinib with various concentrations for IC50 in the activity of RLM. (B) Apatinib with various concentrations for IC50 in the activity of HLM. (C) Icotinib with various concentrations for IC50 in the activity of RLM. (D) Icotinib with various concentrations for IC50 in the activity of HLM. Data are presented as the means ± SD, n = 3.
Figure 4
Figure 4. The concentration-time curve of oxycodone in the experimental and control groups.
(A) Icotinib and (B) apatinib. Data are presented as the means ± SD, n = 6.
Figure 5
Figure 5. Lineweaver-Burk plot and the secondary plot for Ki in RLM/HLM.
Lineweaver-Burk plot and the secondary plot for Ki in the inhibition of oxycodone. (A) Icotinib and (B) apatinib with various concentrations in RLMs. Lineweaver-Burk plot and the secondary plot for Ki in the inhibition of oxycodone metabolism by (C) icotinib and (D) apatinib with various concentrations in HLMs. Data are presented as the means ± SD, n = 3.
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