Association of CYP2C19*2 and associated haplotypes with lower norendoxifen concentrations in tamoxifen-treated Asian breast cancer patients

British Journal of Clinical Pharmacology
Joanne S L LimBalram Chowbay

Abstract

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. 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 chromatography–mass spectrometry. Non-parametric tests and regression methods were implemented to evaluate genotypic–phenotypic associations and haplotypic effects of the SNPs. 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: ...Continue Reading

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Citations

Feb 1, 2018·Clinical Pharmacology and Therapeutics·Matthew P GoetzTeri E Klein
Apr 23, 2019·Expert Review of Clinical Pharmacology·A B Sanchez-SpitmanH J Guchelaar
Dec 16, 2020·Expert Opinion on Drug Metabolism & Toxicology·Ondřej SlanařMartin Šíma
Jan 13, 2021·Scientific Reports·A B Sanchez-SpitmanH J Guchelaar

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