<i>CYP2D6</i> Genotype Predicts Plasma Concentrations of Tamoxifen Metabolites in Ethiopian Breast Cancer Patients

• Main Authors: Jemal Hussien Ahmed, Eyasu Makonnen, Alan Fotoohi, Abraham Aseffa, Rawleigh Howe, Eleni Aklillu
• Format: Article
• Language: English
• Published: MDPI AG 2019-09-01
• Series: Cancers
• Subjects: tamoxifen; endoxifen; pharmacokinetics; pharmacogenetics; <i>CYP2D6</i>; <i>ABCB1</i>; breast cancer
• Online Access: https://www.mdpi.com/2072-6694/11/9/1353

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 (<i>Z</i>)-endoxifen (E) were quantified using LC-MS/MS. Genotyping for <i>CYP2D6, CYP2C9, CYP2C19, CYP3A5, POR,</i> and <i>ABCB1</i> and <i>UGT2B1</i>5 and copy number variation for <i>CYP2D6</i> were done. The proportion of patients with low endoxifen level (&lt;5.9 ng/mL) was 35.8% (median concentration 7.94 ng/mL). The allele frequency of <i>CYP2D6</i> 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 <i>CYP2D6</i> gene. An increase in <i>CYP2D6</i> activity score was associated with increased endoxifen concentration and MR_E/NDM (<i>p</i> &lt; 0.001). The IIV in endoxifen concentration and MR_E/NDM was 74.6% and 59%, respectively. <i>CYP2D6</i> diplotype explained 28.2% and 44% of the variability in absolute endoxifen concentration and MR_E/NDM, respectively. The explanatory power of <i>CYP2D6</i> diplotype was improved among <i>ABCB1c</i>.<i>4036G</i> carriers (43% and 65.2%, respectively for endoxifen concentration and MR_E/NDM) compared to <i>A/A</i> genotype. <i>CYP2C9</i>, <i>CYP2C19</i>, and <i>CYP3A5</i> genotypes had no significant influence on endoxifen concentration or MR_E/NDM. In conclusion, we report a high rate of low endoxifen level as well as large IIV in tamoxifen and its metabolite concentrations. <i>CYP2D6</i> is significant predictor of plasma endoxifen level in a gene-dose dependent manner.