The Effects of AT-533 and AT-533 gel on Liver Cytochrome P450 Enzymes in Rats

Eur J Drug Metab Pharmacokinet. 2022 May;47(3):345-352. doi: 10.1007/s13318-022-00757-w. Epub 2022 Feb 9.

Abstract

Background and objectives: AT-533 is a novel heat shock protein 90 inhibitor, which exhibits various biological activities in vitro and in vivo. Cytochrome P450 (CYP) enzymes in the liver are involved in the biotransformation of drugs and considered to be essential indicators of liver toxicity. The aim of this study was to assess the effect of AT-533, either as active pharmaceutical ingredient or in gel form, on liver CYP enzymes.

Methods: The effect of AT-533 or AT-533 gel on rat liver cytochrome P450 enzymes, including CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, was analyzed using LC-MS/MS.

Results: AT-533 and AT-533 gel did not significantly increase or reduce the enzymatic activity of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 at any treatment dose.

Conclusions: AT-533 and AT-533 gel did not have any effect on CYP activity and may be considered safe for external use in gel form, as an alternative to conventional treatment.

MeSH terms

  • Animals
  • Chromatography, Liquid
  • Cytochrome P-450 CYP1A2* / metabolism
  • Cytochrome P-450 CYP2C19 / metabolism
  • Cytochrome P-450 CYP2C9 / metabolism
  • Cytochrome P-450 CYP2D6 / metabolism
  • Cytochrome P-450 CYP3A / metabolism
  • Cytochrome P-450 Enzyme System / metabolism
  • Indazoles
  • Liver / metabolism
  • Microsomes, Liver* / metabolism
  • Rats
  • Tandem Mass Spectrometry

Substances

  • AT-533
  • Indazoles
  • Cytochrome P-450 Enzyme System
  • Cytochrome P-450 CYP2C9
  • Cytochrome P-450 CYP1A2
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 CYP2D6
  • Cytochrome P-450 CYP3A