ArticleFrontiers in pharmacology2012
Physiologically Based Pharmacokinetic Modeling of Tamoxifen and its Metabolites in Women of Different CYP2D6 Phenotypes Provides New Insight into the Tamoxifen Mass Balance.
Article in Frontiers in pharmacology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers, 1 of them a synthesis that pooled it.
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Who cites it
19 citing papers in PubMed, 1 synthesis or guideline pooled it, 42 citations in OpenAlex.
- Utility of physiologically based pharmacokinetic (PBPK) modeling in oncology drug development and its accuracy: a systematic review.European journal of clinical pharmacology · 2018Pooled it
- Design-ExpertPharmaceutics · 2026Article
- Utilizing Physiologically Based Pharmacokinetic Models to Support Rational Medication in Chinese Elderly Population.Drug design, development and therapy · 2025Article
- Repositioning of Tamoxifen in Surface-Modified Nanocapsules as a Promising Oral Treatment for Visceral Leishmaniasis.Pharmaceutics · 2021Article
- Phenoconversion of Cytochrome P450 Metabolism: A Systematic Review.Journal of clinical medicine · 2020Review
- Tamoxifen in horses: pharmacokinetics and safety study.Irish veterinary journal · 2019Article
- Physiologically based pharmacokinetic modelling of atomoxetine with regard to CYP2D6 genotypes.Scientific reports · 2018Article
- Applied Concepts in PBPK Modeling: How to Extend an Open Systems Pharmacology Model to the Special Population of Pregnant Women.CPT: pharmacometrics & systems pharmacology · 2018Article
- Application of PBPK Modeling and Virtual Clinical Study Approaches to Predict the Outcomes of CYP2D6 Genotype-Guided Dosing of Tamoxifen.CPT: pharmacometrics & systems pharmacology · 2018Article
- 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
- Clinically Relevant Concentrations of Anticancer Drugs: A Guide for Nonclinical Studies.Clinical cancer research : an official journal of the American Association for Cancer Research · 2017Review
- Addressing Adherence Using Genotype-Specific PBPK Modeling-Impact of Drug Holidays on Tamoxifen and Endoxifen Plasma Levels.Frontiers in pharmacology · 2017Article
- Physiologically-based pharmacokinetic models: approaches for enabling personalized medicine.Journal of pharmacokinetics and pharmacodynamics · 2016Review
- A physiome interoperability roadmap for personalized drug development.Interface focus · 2016Article
- Population pharmacokinetic modelling to assess the impact of CYP2D6 and CYP3A metabolic phenotypes on the pharmacokinetics of tamoxifen and endoxifen.British journal of clinical pharmacology · 2014Article
- Measuring selective estrogen receptor modulator (SERM)-membrane interactions with second harmonic generation.Journal of the American Chemical Society · 2014Article
- A nation-wide multicenter 10-year (1999-2008) retrospective clinical study of endocrine therapy for Chinese females with breast cancer.PloS one · 2014Article
- Concomitant use of tamoxifen and endoxifen in postmenopausal early breast cancer: prediction of plasma levels by physiologically-based pharmacokinetic modeling.SpringerPlus · 2014Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Tamoxifen is a first-line endocrine agent in the mechanism-based treatment of estrogen receptor positive (ER(+)) mammary carcinoma and applied to breast cancer patients all over the world. Endoxifen is a secondary and highly active metabolite of tamoxifen that is formed among others by the polymorphic cytochrome P450 2D6 (CYP2D6). It is widely accepted that CYP2D6 poor metabolizers exert a pronounced decrease in endoxifen steady-state plasma concentrations compared to CYP2D6 extensive metabolizers. Nevertheless, an in-depth understanding of the chain of cause and effect between CYP2D6 genotype, endoxifen steady-state plasma concentration, and subsequent tamoxifen treatment benefit still remains to be evolved. In this study, physiologically based pharmacokinetic (PBPK)-modeling was applied to mechanistically investigate the impact of CYP2D6 phenotype on endoxifen formation in female breast cancer patients undergoing tamoxifen therapy. A PBPK-model of tamoxifen and its pharmacologically important metabolites N-desmethyltamoxifen (NDM-TAM), 4-hydroxytamoxifen (4-OH-TAM), and endoxifen was developed and validated. This model is able to simulate the pharmacokinetics (PK) after single and repeated oral tamoxifen doses in female breast cancer patients in dependence of the CYP2D6 phenotype. A detailed model-based analysis of the mass balance offered support for a recent hypothesis stating a more prominent role for endoxifen formation from 4-OH-TAM. In the future this model provides a good basis to further investigate the linkage of PK, mode of action, and treatment outcome in dependence of factors such as phenotype, ethnicity, or co-treatment with CYP2D6 inhibitors.
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