Inhibition of drug metabolizing cytochrome P450s by the aromatase inhibitor drug letrozole and its major oxidative metabolite 4,4'-methanol-bisbenzonitrile in vitro.
Article Details
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Jeong S, Woo MM, Flockhart DA, Desta Z
Inhibition of drug metabolizing cytochrome P450s by the aromatase inhibitor drug letrozole and its major oxidative metabolite 4,4'-methanol-bisbenzonitrile in vitro.
Cancer Chemother Pharmacol. 2009 Oct;64(5):867-75. doi: 10.1007/s00280-009-0935-7. Epub 2009 Feb 7.
- PubMed ID
- 19198839 [ View in PubMed]
- Abstract
PURPOSE: To determine the inhibitory potency of letrozole and its main human metabolite, 4,4'-methanol-bisbenzonitrile, on the activities of eight cytochrome P450 (CYP) enzymes. METHODS: Letrozole and its metabolite were incubated with human liver microsomes (HLMs) (or expressed CYP isoforms) and NADPH in the absence (control) and presence of the test inhibitor. RESULTS: Letrozole was a potent competitive inhibitor of CYP2A6 (K (i) 4.6 +/- 0.05 microM and 5.0 +/- 2.4 microM in HLMs and CYP2A6, respectively) and a weak inhibitor of CYP2C19 (K (i) 42.2 microM in HLMs and 33.3 microM in CYP2C19), while its metabolite showed moderate inhibition of CYP2C19 and CYP2B6. Letrozole or its metabolite had negligible effect on other CYPs. CONCLUSIONS: Based on the in vitro K (i) values, letrozole is predicted to be a weak inhibitor of CYP2A6 in vivo. Letrozole and its major human metabolite show inhibitory activity towards other CYPs, but clinically relevant drug interactions seem less likely as the K (i) values are above the therapeutic plasma concentrations of letrozole.
DrugBank Data that Cites this Article
- Drugs
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Letrozole Cytochrome P450 2A6 Protein Humans UnknownSubstrateInhibitorDetails Letrozole Cytochrome P450 3A4 Protein Humans UnknownSubstrateDetails - Drug Reactions
Reaction Details - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareMethadoneAminoglutethimide The serum concentration of Methadone can be increased when it is combined with Aminoglutethimide. MethadoneTestolactone The serum concentration of Methadone can be increased when it is combined with Testolactone. MethadoneExemestane The serum concentration of Methadone can be increased when it is combined with Exemestane. MethadoneLetrozole The serum concentration of Methadone can be increased when it is combined with Letrozole. MethadoneAnastrozole The serum concentration of Methadone can be increased when it is combined with Anastrozole.
