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Bioactivation of flutamide metabolites by human liver microsomes

Ping Kang1, Deepak Dalvie, Evan Smith

  • 1Pharmacokinetics, Dynamics, and Metabolism Department, Pfizer Global Research and Development, 10724 Science Center Drive, San Diego, CA 92121, USA. ping.kang@pfizer.com

Drug Metabolism and Disposition: the Biological Fate of Chemicals
|April 16, 2008
PubMed

Insights

Flutamide's toxic effects on the liver may stem from its metabolites, not just the parent drug. Researchers identified specific glutathione adducts formed by flutamide metabolites, indicating a broader mechanism for drug-induced liver injury.

Area of Science:

  • Pharmacology
  • Drug Metabolism
  • Hepatotoxicity

Background:

  • Flutamide, a nonsteroidal antiandrogen, treats prostate cancer but can cause rare liver damage.
  • Drug bioactivation and covalent binding to proteins are suspected causes of flutamide toxicity.
  • Previous studies identified an N-S glutathione adduct from flutamide bioactivation.

Purpose of the Study:

  • To investigate the cytochrome P450 (P450)-mediated bioactivation of flutamide metabolites in human liver microsomes.
  • To identify reactive species formed during flutamide metabolism using reduced glutathione (GSH) as a trapping agent.
  • To elucidate the comprehensive bioactivation mechanism contributing to flutamide-induced hepatotoxicity.

Main Methods:

  • In vitro studies using human liver microsomes.
  • Incubation of flutamide metabolites with reduced glutathione (GSH).
  • Identification and characterization of GSH adducts using analytical techniques.
  • Investigation using recombinant P450 isozymes (CYP1A2, CYP3A4, CYP2C19).

Main Results:

  • Several GSH adducts (G1, Flu-1-G1, Flu-1-G2, Flu-6-Gs) were identified, derived from flutamide metabolites.
  • A comprehensive bioactivation pathway was proposed, including unusual activation of the metabolite 4-nitro-3-(trifluoromethyl)phenylamine (Flu-1).
  • CYP1A2, CYP3A4, and CYP2C19 were identified as major P450 isozymes involved in flutamide metabolite bioactivation.

Conclusions:

  • Flutamide metabolites, in addition to the parent drug, can undergo bioactivation.
  • These bioactivated metabolites can form reactive species, contributing to flutamide-induced hepatotoxicity.
  • Understanding these pathways is crucial for managing flutamide's liver toxicity risk.

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