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Pharmacokinetics of Tamoxifen and Its Major Metabolites and the Effect of the African Ancestry Specific CYP2D6*17 Variant on the Formation of the Active Metabolite, Endoxifen.

Kanji, Comfort Ropafadzo, Nyabadza, Georgina, Nhachi, Charles and Masimirembwa, Collen (2023) Pharmacokinetics of Tamoxifen and Its Major Metabolites and the Effect of the African Ancestry Specific CYP2D6*17 Variant on the Formation of the Active Metabolite, Endoxifen. Journal of personalized medicine, 13 (2). ISSN 2075-4426

Abstract

Tamoxifen (TAM) is widely used in the treatment of hormone receptor-positive breast cancer. TAM is metabolized into the active secondary metabolite endoxifen (ENDO), primarily by CYP2D6. We aimed to investigate the effects of an African-specific CYP2D6 variant allele, CYP2D6*17, on the pharmacokinetics (PK) of TAM and its active metabolites in 42 healthy black Zimbabweans. Subjects were grouped based on CYP2D6 genotypes as CYP2D6*1/*1 or *1/*2 or *2/*2 (CYP2D6*1 or *2), CYP2D6*1/*17 or 2*/*17, and CYP2D6*17/*17. PK parameters for TAM and three metabolites were determined. The pharmacokinetics of ENDO showed statistically significant differences among the three groups. The mean ENDO AUC0-∞ in CYP2D6*17/*17 subjects was 452.01 (196.94) h·*ng/mL, and the AUC0-∞ in CYP2D6*1/*17 subjects was 889.74 h·ng/mL, which was 5-fold and 2.8-fold lower than in CYP2D6*1 or *2 subjects, respectively. Individuals who were heterozygous or homozygous for CYP2D6*17 alleles showed a 2- and 5-fold decrease in Cmax, respectively, compared to the CYP2D6*1 or *2 genotype. CYP2D6*17 gene carriers have significantly lower ENDO exposure levels than CYP2D6*1 or *2 gene carriers. Pharmacokinetic parameters of TAM and the two primary metabolites, N-desmethyl tamoxifen (NDT) and 4-hydroxy tamoxifen (4OHT), did not show any significant difference in the three genotype groups. The African-specific CYP2D6*17 variant had effects on ENDO exposure levels that could potentially have clinical implications for patients homozygous for this variant.

Item Type: Article
Date Deposited: 13 Apr 2023 00:45
Last Modified: 13 Apr 2023 00:45
URI: https://oak.novartis.com/id/eprint/49051

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