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摘要
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 genotypic-phenotypic 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 (0.38-3.28) vs. 1.28 (0.30-3.36) vs. 1.15 ng ml(-1) (0.26-2.45, P = 0.010)] as well as significantly lower MRNorEND/(Z)-END [GG vs. GA vs. AA: 9.40 (3.27-28.35) vs. 8.15 (2.67-18.9) vs. 6.06 (4.47-14.6), P < 0.0001] andMR(NorEND/NDDM) [GG vs. GA vs. AA: 2.75 (0.62-6.26) vs. 2.43 (0.96-4.18) vs. 1.75 (1.10-2.49), 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. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Most studies have investigated the associations between CYP2D6 variants and tamoxifen pharmacokinetics, but the impact of CYP2C19 genetic variants on tamoxifen disposition has been less extensively studied. Recent findings suggest that a tertiary metabolite of tamoxifen, 4-hydroxy-N,N-didesmethyltamoxifen or norendoxifen (NorEND), exhibits potent aromatase inhibitory activity and estrogen receptor antagonism. To date, the influence of CYP2C19 polymorphisms and haplotypes on the pharmacokinetics of NorEND is not known. WHAT THIS STUDY ADDS Of the 66 CYP2C19 polymorphisms identified in healthy Asians, 14 were found to be tightly linked with CYP2C19*2, CYP2C19*3 and CYP2C19*17. No significant associations were observed between these CYP2C19 functional polymorphisms and their linked SNPs with the steady-state concentrations of tamoxifen, N-desmethyltamoxifen (NDM), (Z)-4-hydroxytamoxifen and (Z)-endoxifen. However, two other potentially important metabolites, N, N-didesmethyltamoxifen (NDDM) and NorEND were genetically associated. The CYP2C19 H2 haplotype, which included CYP2C19*2, was significantly correlated with lower plasma concentrations of NorEND, and metabolic ratios MRNorEND/ NDDM (P < 0.0001) and MRNorEND/(Z)-END (P = 0.001), indicating significantly lower formation rates of NorEND.
- 出版日期2016-6
