ArticleBritish journal of clinical pharmacology2014
Population pharmacokinetic modelling to assess the impact of CYP2D6 and CYP3A metabolic phenotypes on the pharmacokinetics of tamoxifen and endoxifen.
Article in British journal of clinical pharmacology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 25 citations in OpenAlex.
- ESR1 and p53 interactome alteration defines mechanisms of tamoxifen response in luminal breast cancer.iScience · 2024Article
- Personalizing Personalized Medicine: The Confluence of Pharmacogenomics, a Person's Medication Experience and Ethics.Pharmacy (Basel, Switzerland) · 2023Review
- Review
- Population Pharmacokinetics of Z-Endoxifen in Patients With Advanced Solid Tumors.Journal of clinical pharmacology · 2022Article
- Gut microbiota and host Cyp450s co-contribute to pharmacokinetic variability in mice with non-alcoholic steatohepatitis: Effects vary from drug to drug.Journal of advanced research · 2022Article
- Population Pharmacokinetics of Ibrutinib and Its Dihydrodiol Metabolite in Patients with Lymphoid Malignancies.Clinical pharmacokinetics · 2020Observational
- Integrated Data Analysis of Six Clinical Studies Points Toward Model-Informed Precision Dosing of Tamoxifen.Frontiers in pharmacology · 2020Article
- The Underrated Risks of Tamoxifen Drug Interactions.European journal of drug metabolism and pharmacokinetics · 2018Review
- The formation of estrogen-like tamoxifen metabolites and their influence on enzyme activity and gene expression of ADME genes.Archives of toxicology · 2018Article
- Exploiting Pharmacokinetic Models of Tamoxifen and Endoxifen to Identify Factors Causing Subtherapeutic Concentrations in Breast Cancer Patients.Clinical pharmacokinetics · 2018Article
- Improved Prediction of Endoxifen Metabolism by CYP2D6 Genotype in Breast Cancer Patients Treated with Tamoxifen.Frontiers in pharmacology · 2017Article
- Article
- Effects of Pharmacogenetics on the Pharmacokinetics and Pharmacodynamics of Tamoxifen.Clinical pharmacokinetics · 2015Review
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Authors and funding
7 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aimsTamoxifen is considered a pro-drug of its active metabolite endoxifen. The major metabolic enzymes involved in endoxifen formation are CYP2D6 and CYP3A. There is considerable evidence that variability in activity of these enzymes influences endoxifen exposure and thereby may influence the clinical outcome of tamoxifen treatment. We aimed to quantify the impact of metabolic phenotype on the pharmacokinetics of tamoxifen and endoxifen.
methodsWe assessed the CYP2D6 and CYP3A metabolic phenotypes in 40 breast cancer patients on tamoxifen treatment with a single dose of dextromethorphan as a dual phenotypic probe for CYP2D6 and CYP3A. The pharmacokinetics of dextromethorphan, tamoxifen and their relevant metabolites were analyzed using non-linear mixed effects modelling.
resultsPopulation pharmacokinetic models were developed for dextromethorphan, tamoxifen and their metabolites. In the final model for tamoxifen, the dextromethorphan derived metabolic phenotypes for CYP2D6 as well as CYP3A significantly (P < 0.0001) explained 54% of the observed variability in endoxifen formation (inter-individual variability reduced from 55% to 25%).
conclusionsWe have shown that not only CYP2D6, but also CYP3A enzyme activity influences the tamoxifen to endoxifen conversion in breast cancer patients. Our developed model may be used to assess separately the impact of CYP2D6 and CYP3A mediated drug-drug interactions with tamoxifen without the necessity of administering this anti-oestrogenic drug and to support Bayesian guided therapeutic drug monitoring of tamoxifen in routine clinical practice.
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