Association of CYP2C19*2 and associated haplotypes with lower norendoxifen concentrations in tamoxifen-treated Asian breast cancer patients.
Br J Clin Pharmacol
; 81(6): 1142-52, 2016 06.
Article
em En
| MEDLINE
| ID: mdl-26799162
ABSTRACT
AIM:
The aim was to examine the influence of CYP2C19 variants and associated haplotypes on the disposition of tamoxifen and its metabolites, particularly norendoxifen (NorEND), in Asian patients with breast cancer.METHODS:
Sixty-six CYP2C19 polymorphisms were identified in healthy Asians (n = 240), of which 14 were found to be tightly linked with CYP2C19*2, CYP2C19*3 and CYP2C19*17. These 17 SNPs were further genotyped in Asian breast cancer patients receiving tamoxifen (n = 201). Steady-state concentrations of tamoxifen and its metabolites were quantified using liquid chromatographymass spectrometry. Non-parametric tests and regression methods were implemented to evaluate genotypicphenotypic associations and haplotypic effects of the SNPs.RESULTS:
CYP2C19 functional polymorphisms and their linked SNPs were not significantly associated with plasma concentrations of tamoxifen and its main metabolites N-desmethyltamoxifen, (Z)-4-hydroxytamoxifen and (Z)-Endoxifen. However, CYP2C19*2 and its seven linked SNPs were significantly associated with lower NorEND concentrations, MRNorEND/NDDM and MRNorEND/(Z)-END. Specifically, patients carrying the CYP2C19*2 variant allele A had significantly lower NorEND concentrations [median (range), GG vs. GA vs. AA 1.51 (0.383.28) vs. 1.28 (0.303.36) vs. 1.15 ng ml−1 (0.262.45, P = 0.010)] as well as significantly lower MRNorEND/(Z)-END [GG vs. GA vs. AA 9.40 (3.2728.35) vs. 8.15 (2.6718.9) vs. 6.06 (4.4714.6), P < 0.0001] and MRNorEND/NDDM [GG vs. GA vs. AA 2.75 (0.626.26) vs. 2.43 (0.964.18) vs. 1.75 (1.102.49), P < 0.00001]. CYP2C19 H2 haplotype, which included CYP2C19*2, was also significantly associated with lower NorEND concentrations (P = 0.0020), MRNorEND/NDDM (P < 0.0001) and MRNorEND/(Z)-END (P < 0.0001), indicating significantly lower formation rates of NorEND.CONCLUSION:
These data highlight the potential relevance of CYP2C19 pharmacogenetics in influencing NorEND concentrations in tamoxifen-treated patients, which may influence treatment outcomes.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Tamoxifeno
/
Neoplasias da Mama
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Antineoplásicos Hormonais
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Citocromo P-450 CYP2C19
Tipo de estudo:
Risk_factors_studies
Limite:
Adult
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Aged
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Female
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Humans
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Middle aged
Idioma:
En
Revista:
Br J Clin Pharmacol
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Singapura