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Effects of multi-kinase inhibitors on the activity of cytochrome P450 2J2

Ayaka Kojima1, Masayuki Nadai1, Norie Murayama2

  • 1Laboratory of Pharmaceutics, Faculty of Pharmacy, Meijo University, Nagoya, Japan.

Xenobiotica; the Fate of Foreign Compounds in Biological Systems
|October 17, 2022
PubMed

Insights

Apatinib, motesanib, and vatalanib strongly inhibit Cytochrome P450 2J2 (CYP2J2) activity. This suggests potential alterations in CYP2J2 substrate effects when these multi-kinase inhibitors are administered alongside other drugs.

Area of Science:

  • Pharmacology
  • Biochemistry
  • Oncology

Background:

  • Cytochrome P450 2J2 (CYP2J2) is highly expressed in extrahepatic tissues and tumors.
  • CYP2J2 metabolizes arachidonic acid (AA) to epoxyeicosatrienoic acids (EETs), which promote tumor growth by inhibiting apoptosis.
  • Multi-kinase inhibitors (MKIs) are antitumor drugs that warrant investigation for their effects on CYP2J2.

Purpose of the Study:

  • To determine the inhibitory effects of MKIs on CYP2J2 activity.
  • To investigate if MKIs affect CYP2J2-catalyzed EET formation from AA.

Main Methods:

  • Assessed inhibition of astemizole O-demethylation by 20 MKIs in CYP2J2.
  • Determined inhibition constants (Ki) for potent inhibitors.
  • Investigated inhibition of CYP2J2-catalyzed 14,15-EET formation from AA.
  • Performed molecular docking simulations of MKIs with CYP2J2.

Main Results:

  • Apatinib, motesanib, and vatalanib showed potent inhibition of CYP2J2 activity.
  • These MKIs exhibited competitive inhibition with low Ki values (9.3, 15.4, and 65.0 nM, respectively).
  • Apatinib, motesanib, and vatalanib also inhibited CYP2J2-catalyzed 14,15-EET formation from AA.
  • Docking simulations revealed favorable binding energies for these three MKIs with CYP2J2.

Conclusions:

  • Apatinib, motesanib, and vatalanib are strong inhibitors of CYP2J2.
  • These MKIs may alter the metabolic effects of CYP2J2 substrates.
  • Clinical implications regarding drug-drug interactions involving CYP2J2 substrates and these MKIs should be considered.
Keywords:
CYP2J2Kiepoxyeicosatrienoic acidinhibitionmulti-kinase inhibitor

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