Effect of apatinib on the pharmacokinetics of tramadol and O-desmethyltramadol in rats

PeerJ. 2023 Sep 11:11:e16051. doi: 10.7717/peerj.16051. eCollection 2023.

Abstract

Since the combination of anticancer drugs and opioids is very common, apatinib and tramadol are likely to be used in combination clinically. This study evaluated the effects of apatinib on the pharmacokinetics of tramadol and its main metabolite O-desmethyltramadol in Sprague-Dawley (SD) rats and the inhibitory effects of apatinib on tramadol in rat liver microsomes (RLMs), human liver microsomes (HLMs) and recombinant human CYP2D6.1. The samples were determined by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The in vivo results showed that compared with the control group, apatinib increased the AUC(0-t), AUC(0-∞) and Cmax values of tramadol and O-desmethyltramadol, and decreased the values of VZ/F and CLz/F. In addition, the MRT(0-t), MRT(0-∞) values of O-desmethyltramadol were increased. In vitro, apatinib inhibited the metabolism of tramadol by a mixed way with IC50 of 1.927 µM in RLMs, 2.039 µM in HLMs and 15.32 µM in CYP2D6.1. In summary, according to our findings, apatinib has a strong in vitro inhibitory effect on tramadol, and apatinib can increase the analgesic effect of tramadol and O-desmethyltramadol in rats.

Keywords: Apatinib; Drug inhibition; Metabolism; O-desmethyltramadol; Pharmacokinetics; Tramadol.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chromatography, Liquid
  • Cytochrome P-450 CYP2D6
  • Humans
  • Microsomes, Liver
  • Rats
  • Rats, Sprague-Dawley
  • Tandem Mass Spectrometry
  • Tramadol* / pharmacology

Substances

  • O-demethyltramadol
  • Tramadol
  • apatinib
  • Cytochrome P-450 CYP2D6

Grants and funding

This work was supported by the Wenzhou Municipal Science and Technology Bureau (Y2022089), the National Key Research and Development Program of China (2020YFC2008301), the National Natural Science Foundation of China (NSFC 81973397), the Natural Science Foundation of Zhejiang Province (LBY21H070001) and the Wenzhou Municipal Science and Technology Bureau (Y20180594). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.