In vitro cytochrome P450-mediated metabolism of exemestane

Landry K. Kamdem, David A. Flockhart, Zeruesenay Desta

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

Exemestane is a potent and irreversible steroidal aromatase inhibitor drug used for the treatment of estrogen receptor-positive breast cancer. Our aim was to identify and assess the contribution of the specific cytochromes P450 (P450s) responsible for exemestane primary in vitro metabolism. With the use of high-performance liquid chromatography and liquid chromatography-tandem mass spectrometry analytical techniques, 17-hydroexemestane (MI) formation and 6-hydroxymethylexemestane (MII) formation were found to be the predominant exemestane metabolic pathways. In a bank of 15 well characterized human liver microsomes with known P450 isoform-specific activities, the MI formation rate correlated significantly with CYP1A2 (Spearman r = 0.60, p = 0.02) and CYP4A11 (Spearman r = 0.67, p = 0.01) isoform-specific activities, whereas the MII production rate significantly correlated with CYP2B6 (Spearman r = 0.57, p = 0.03) and CYP3A (Spearman r = 0.76, p = 0.005) isoform-specific activities. Recombinant CYP1A1 metabolized exemestane to MI with a catalytic efficiency (Clint) of 150 nl/pmol P450 × min that was at least 3.5-fold higher than those of other P450s investigated. Recombinant CYP3A4 catalyzed MII formation from exemestane with a catalytic efficiency of 840 nl/ pmol P450 × min that was at least 4-fold higher than those of other P450s investigated. Among a panel of 10 chemical inhibitors tested, only ketoconazole and troleandomycin (CYP3A-specific chemical inhibitors) significantly inhibited the formation of MII by 45 and 95%, respectively. None of them markedly inhibited the formation of MI. In summary, exemestane seems to be metabolized to MI by multiple P450s that include CYP4A11 and CYP1A1/2, whereas its oxidation to MII is primarily mediated by CYP3A.

Original languageEnglish
Pages (from-to)98-105
Number of pages8
JournalDrug Metabolism and Disposition
Volume39
Issue number1
DOIs
StatePublished - Jan 2011

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exemestane
Cytochrome P-450 Enzyme System
Cytochrome P-450 CYP3A
Protein Isoforms
Cytochrome P-450 CYP1A1
Troleandomycin
Cytochrome P-450 CYP1A2
Aromatase Inhibitors
Ketoconazole
Liver Microsomes
Tandem Mass Spectrometry
Metabolic Networks and Pathways
Liquid Chromatography
Estrogen Receptors
In Vitro Techniques
High Pressure Liquid Chromatography

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

Cite this

In vitro cytochrome P450-mediated metabolism of exemestane. / Kamdem, Landry K.; Flockhart, David A.; Desta, Zeruesenay.

In: Drug Metabolism and Disposition, Vol. 39, No. 1, 01.2011, p. 98-105.

Research output: Contribution to journalArticle

Kamdem, Landry K. ; Flockhart, David A. ; Desta, Zeruesenay. / In vitro cytochrome P450-mediated metabolism of exemestane. In: Drug Metabolism and Disposition. 2011 ; Vol. 39, No. 1. pp. 98-105.
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