Inhibition of drug metabolizing cytochrome P450s by the aromatase inhibitor drug letrozole and its major oxidative metabolite 4,4′-methanol-bisbenzonitrile in vitro
Autor: | Seongwook Jeong, Margaret M. Woo, David A. Flockhart, Zeruesenay Desta |
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Rok vydání: | 2009 |
Předmět: |
Cancer Research
Cytochrome medicine.drug_class Metabolite Antineoplastic Agents Pharmacology Toxicology Article chemistry.chemical_compound Nitriles medicine Cytochrome P-450 Enzyme Inhibitors Humans Pharmacology (medical) Aromatase inhibitor biology Aromatase Inhibitors Chemistry Letrozole Cytochrome P450 Triazoles Drug interaction Kinetics Oncology Biochemistry Enzyme inhibitor Area Under Curve Microsomes Liver biology.protein NADP medicine.drug |
Zdroj: | Cancer Chemotherapy and Pharmacology. 64:867-875 |
ISSN: | 1432-0843 0344-5704 |
Popis: | 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.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.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.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. |
Databáze: | OpenAIRE |
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