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CYP2D6 Genotype Predicts Plasma Concentrations of Tamoxifen Metabolites in Ethiopian Breast Cancer Patients - PubMed

  • ️Tue Jan 01 2019

CYP2D6 Genotype Predicts Plasma Concentrations of Tamoxifen Metabolites in Ethiopian Breast Cancer Patients

Jemal Hussien Ahmed et al. Cancers (Basel). 2019.

Abstract

Tamoxifen displays wide inter-individual variability (IIV) in its pharmacokinetics and treatment outcome. Data on tamoxifen pharmacokinetics and pharmacogenetics from black African breast cancer patient populations is lacking. We investigated the pharmacokinetic and pharmacogenetic profile of tamoxifen and its major active metabolite, endoxifen, in Ethiopian breast cancer patients. A total of 81 female breast cancer patients on adjuvant tamoxifen therapy were enrolled. Tamoxifen (Tam) and its major metabolites, N-desmethyltamoxifen (NDM), 4-hydroxy-tamoxifen (4-HT), and (Z)-endoxifen (E) were quantified using LC-MS/MS. Genotyping for CYP2D6, CYP2C9, CYP2C19, CYP3A5, POR, and ABCB1 and UGT2B15 and copy number variation for CYP2D6 were done. The proportion of patients with low endoxifen level (<5.9 ng/mL) was 35.8% (median concentration 7.94 ng/mL). The allele frequency of CYP2D6 gene deletion (*5) and duplication (*1×N or *2×N) was 4.3% and 14.8%, respectively. Twenty-six percent of the patients carried duplicated or multiplicated CYP2D6 gene. An increase in CYP2D6 activity score was associated with increased endoxifen concentration and MRE/NDM (p < 0.001). The IIV in endoxifen concentration and MRE/NDM was 74.6% and 59%, respectively. CYP2D6 diplotype explained 28.2% and 44% of the variability in absolute endoxifen concentration and MRE/NDM, respectively. The explanatory power of CYP2D6 diplotype was improved among ABCB1c.4036G carriers (43% and 65.2%, respectively for endoxifen concentration and MRE/NDM) compared to A/A genotype. CYP2C9, CYP2C19, and CYP3A5 genotypes had no significant influence on endoxifen concentration or MRE/NDM. In conclusion, we report a high rate of low endoxifen level as well as large IIV in tamoxifen and its metabolite concentrations. CYP2D6 is significant predictor of plasma endoxifen level in a gene-dose dependent manner.

Keywords: ABCB1; CYP2D6; breast cancer; endoxifen; pharmacogenetics; pharmacokinetics; tamoxifen.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1

Scatter plot showing the Pearson’s correlation between endoxifen versus tamoxifen (A), N-desmethyl-tamoxifen versus tamoxifen (B) and 4-hydroxy-tamoxifen versus tamoxifen (C), endoxifen versus N-desmethyl-tamoxifen (D) and endoxifen versus 4-hydroxy-tamoxifen (E).

Figure 2
Figure 2

Plasma concentration of endoxifen and metabolic ratio (MRE/NDM) by CYP2D6 diplotype (A) and phenotype (B).

Figure 3
Figure 3

Plasma endoxifen concentration and metabolic ratios (MRE/NDM and MRE/4-HT) plotted by POR (A) or ABCB1 c.4036A>G genotype (B,C).

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