Effects of Genetic Polymorphisms of Drug Metabolizing Enzymes and co-Medications on Tamoxifen Metabolism in Black South African Women with Breast Cancer.
Journal
Clinical pharmacology and therapeutics
ISSN: 1532-6535
Titre abrégé: Clin Pharmacol Ther
Pays: United States
ID NLM: 0372741
Informations de publication
Date de publication:
07 2023
07 2023
Historique:
received:
23
01
2023
accepted:
02
04
2023
medline:
20
6
2023
pubmed:
13
4
2023
entrez:
12
4
2023
Statut:
ppublish
Résumé
Clinical outcomes of tamoxifen (TAM) treatment show wide interindividual variability. Comedications and genetic polymorphisms of enzymes involved in TAM metabolism contributes to this variability. Drug-drug and drug-gene interactions have seldom been studied in African Black populations. We evaluated the effects of commonly co-administered medicines on TAM pharmacokinetics in a cohort of 229 South African Black female patients with hormone-receptor positive breast cancer. We also investigated the pharmacokinetic effects of genetic polymorphism in enzymes involved in TAM metabolism, including the variants CYP2D6*17 and *29, which have been mainly reported in people of African descent. TAM and its major metabolites, N-desmethyltamoxifen (NDM), 4-OH-tamoxifen, and endoxifen (ENDO), were quantified in plasma using the liquid chromatography-mass spectrometry. The GenoPharm open array was used to genotype CYP2D6, CYP3A5, CYP3A4, CYP2B6, CYP2C9, and CYP2C19. Results showed that CYP2D6 diplotype and CYP2D6 phenotype significantly affected endoxifen concentration (P < 0.001 and P < 0.001). CYP2D6*17 and CYP2D6*29 significantly reduced the metabolism of NDM to ENDO. Antiretroviral therapy had a significant effect on NDM levels and the TAM/NDM and NDM/ENDO metabolic ratios but did not result in significant effects on ENDO levels. In conclusion, CYP2D6 polymorphisms affected endoxifen concentration and the variants CYP2D6*17 and CYP2D6*29 significantly contributed to low exposure levels of ENDO. This study also suggests a low risk of drug-drug interaction in patients with breast cancer on TAM.
Substances chimiques
4-hydroxy-N-desmethyltamoxifen
46AF8680RC
Cytochrome P-450 CYP2D6
EC 1.14.14.1
N-desmethyltamoxifen
OOJ759O35C
Tamoxifen
094ZI81Y45
Antineoplastic Agents, Hormonal
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
127-136Subventions
Organisme : NCI NIH HHS
ID : P30 CA013696
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA250012
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA192627
Pays : United States
Informations de copyright
© 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.
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