Celecoxib is a substrate of CYP2D6: Impact on celecoxib metabolism in individuals with CYP2C9*3 variants.
Drug Metab Pharmacokinet
; 33(5): 219-227, 2018 Oct.
Article
en En
| MEDLINE
| ID: mdl-30219715
ABSTRACT
Celecoxib was characterized as a substrate of human cytochrome P450 (CYP) 2D6 in vitro. In recombinant CYP2D6, celecoxib hydroxylation showed atypical substrate inhibition kinetics with apparent Km, Ki, and Vmax of 67.2 µM, 12.6 µM, and 1.33 µM/min, respectively. In human liver microsomes (HLMs), a concentration-dependent inhibition of celecoxib hydroxylation by quinidine was observed after CYP2C9 and CYP3A4 were inhibited. In individual HLMs with variable CYP2D6 activities, a significant correlation was observed between celecoxib hydroxylation and CYP2D6-selective dextromethorphan O-demethylation when CYP2C9 and CYP3A4 activities were suppressed (r = 0.97, P < 0.0001). Molecular modeling showed two predominant docking modes of celecoxib with CYP2D6, resulting in either a substrate or an inhibitor. A second allosteric binding antechamber, which stabilized the inhibition mode, was revealed. Modeling results were consistent with the observed substrate inhibition kinetics. Using HLMs from individual donors, the relative contribution of CYP2D6 to celecoxib metabolism was found to be highly variable and dependent on CYP2C9 genotypes, ranging from no contribution in extensive metabolizers with CYP2C9*1*1 genotype to approximately 30% in slow metabolizers with allelic variants CYP2C9*1*3 and CYP2C9*3*3. These results demonstrate that celecoxib may become a potential victim of CYP2D6-associated drug-drug interactions, particularly in individuals with reduced CYP2C9 activity.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Variación Genética
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Citocromo P-450 CYP2D6
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Citocromo P-450 CYP2C9
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Celecoxib
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Año:
2018
Tipo del documento:
Article