In vitro cytochrome P450-mediated metabolism of exemestane.
Article Details
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Kamdem LK, Flockhart DA, Desta Z
In vitro cytochrome P450-mediated metabolism of exemestane.
Drug Metab Dispos. 2011 Jan;39(1):98-105. doi: 10.1124/dmd.110.032276. Epub 2010 Sep 28.
- PubMed ID
- 20876785 [ View in PubMed]
- 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 (Cl(int)) of 150 nl/pmol P450 x 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 x 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.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Exemestane Cytochrome P450 3A4 Protein Humans UnknownSubstrateDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareExemestanePhenytoin The metabolism of Exemestane can be increased when combined with Phenytoin. ExemestanePentobarbital The metabolism of Exemestane can be increased when combined with Pentobarbital. ExemestaneCarbamazepine The metabolism of Exemestane can be increased when combined with Carbamazepine. ExemestaneMitotane The metabolism of Exemestane can be increased when combined with Mitotane. ExemestanePrimidone The metabolism of Exemestane can be increased when combined with Primidone.