当前位置： SCI文献检索 > EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY期刊下所有文献 > Effect of CYP3A4*22, CYP3A5*3, and CYP3A combined genotypes on tamoxifen metabolism.

Effect of CYP3A4*22, CYP3A5*3, and CYP3A combined genotypes on tamoxifen metabolism.

Abstract：

BACKGROUND:Tamoxifen is one of the cornerstones of endocrine therapy for breast cancer. Recently, the decreased activity CYP3A4*22 allele and the loss of function CYP3A5*3 allele have been described as potential factors that could help to explain the inter-patient variability in tamoxifen metabolism. The aim of this study is to investigate the effect of CYP3A4*22, CYP3A5*3, and CYP3A combined genotypes on tamoxifen metabolism. METHODS:DNA from 667 women enrolled in the CYPTAM study (NTR1509) was genotyped (CYP2D6, CYP3A4*22, and CYP3A5*3). Tamoxifen and metabolite concentrations were measured in serum, and metabolic ratios were calculated. The effect of the CYP3A4*22, CYP3A5*3, and CYP3A combined genotypes in addition to the CYP2D6 genotypes was examined by multiple linear regression analysis. RESULTS:CYP3A4*22 carriers reached significant higher concentrations of tamoxifen, N-desmethyl-tamoxifen, and 4-hydroxy-tamoxifen compared to non-carriers, whereas a tendency toward increased endoxifen levels was observed (p = 0.088). The metabolic ratio tamoxifen/N-desmethyl-tamoxifen was significantly higher in CYP3A4*22 individuals (0.59 vs. 0.52, p < 0.001). At the same time, CYP3A4*22 genotype contributed to improving the inter-variability [R 2 of the (log-transformed) metabolic ratio tamoxifen/N-desmethyl-tamoxifen improved from 21.8 to 23.9%, p < 0.001]. CYP3A5*3 marginally improved the explained variability of the (log transformed) metabolic ratio 4-hydroxy-tamoxifen/endoxifen (from 44.9 to 46.2%, p < 0.038). CONCLUSION:Our data demonstrate that CYP3A genotype has a minor effect to explaining the variability between patients in tamoxifen metabolism and has no added value in addition to CYP2D6 genotype.

journal_name

Eur J Clin Pharmacol

journal_title

European journal of clinical pharmacology

authors

Sanchez Spitman AB,Moes DJAR,Gelderblom H,Dezentje VO,Swen JJ,Guchelaar HJ

doi

10.1007/s00228-017-2323-2

subject

Has Abstract

pub_date

2017-12-01 00:00:00

pages

1589-1598

issue

12

eissn

0031-6970

issn

1432-1041

pii

10.1007/s00228-017-2323-2

journal_volume

73

pub_type

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