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| Content Provider | PubMed Central |
|---|---|
| Author | Kristin, Dickschen Willmann, Stefan Thelen, Kirstin Lippert, Jörg Hempel, Georg Thomas, Eissing |
| Copyright Year | 2012 |
| 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. |
| Related Links | http://dx.doi.org/10.3389/fphar.2012.00092 |
| Starting Page | 92 |
| File Format | |
| ISSN | 16639812 |
| e-ISSN | 16639812 |
| Journal | Frontiers in Pharmacology |
| Volume Number | 3 |
| Language | English |
| Publisher | Frontiers Research Foundation |
| Publisher Date | 2012-01-01 |
| Access Restriction | Open |
| Rights Holder | Frontiers Research Foundation |
| Subject Keyword | Research in Higher Education |
| Content Type | Text |
| Resource Type | Article |
| Subject | Pharmacology Pharmacology (medical) |
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