Metabolism of the antiandrogenic drug (flutamide) by human CYP1A2

Manjunath S. Shet, Michael McPhaul, Charles W. Fisher, Nancy R. Stallings, Ronald W. Estabrook

Research output: Contribution to journalArticlepeer-review

117 Scopus citations


The antiandrogenic drug, flutamide, is widely used in the treatment of carcinoma of the prostate. The present study examines the metabolism of flutamide by human liver microsomes and purified recombinant human cytochrome P450s (CYP), expressed as fusion proteins. These studies show the principal role of CYP1A2 in the metabolism of flutamide to 2-hydroxyflutamide. A minor metabolite is formed during the metabolism of flutamide by CYP3A4 in the presence of an excess of added purified NADPH-P450 reductase. The metabolism of flutamide is inhibited by low concentrations of α-naphthoflavone and ketoconazole. Other substrates of CYP1A2, such as phenacetin, imipramine, caffeine, and estradiol, are also inhibitors of flutamide metabolism' by CYP1A2. Of interest is the inhibition of flutamide metabolism by its metabolite, 2-hydroxyflutamide, and the inhibition of the 2- and 4- hydroxylation of estradiol by flutamide. CV1 cells do not metabolize flutamide to 2-hydroxyflutamide. In assays performed using this cell line transfected with the cDNA for the androgen receptor, flutamide is a pure antagonist, and 2-hydroxyflutamide, while a more potent androgen receptor (AR) antagonist, activates the AR at higher concentrations. Stable expression of CYP1A2 in these CV1 cells causes flutamide to exhibit agonistic properties at higher concentrations, a behavior not exhibited by cells stably transfected only with the expression vector encoding the AR. These findings raise the possibility that increased conversion of flutamide to 2- hydroxyflutamide or accumulation of 2-hydroxyflutamide in cells may contribute to the anomalous responses to flutamide that are observed in some advanced prostate cancers.

Original languageEnglish (US)
Pages (from-to)1298-1303
Number of pages6
JournalDrug Metabolism and Disposition
Issue number11
StatePublished - Nov 1997

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science


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