Dextromethorphan As a Phenotyping Test to Predict Endoxifen Exposure in Patients on Tamoxifen Treatment

Graan, Anne-Joy M. de; Teunissen, Sebastiaan F.; Vos, Filip Yves Francine Léon De; Loos, Walter J.; Schaik, Ron H.N. van; Jongh, Felix E. de; Vos, Aad I. de; Alphen, Robbert J. van; Verweij, Jaap; Seynaeve, Caroline; Beijnen, Jos H.; Mathijssen, Ron H.J.

doi:10.1200/jco.2010.32.9839

Cited by 49 publications

(29 citation statements)

References 44 publications

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“…This was strikingly demonstrated in a patient who was also receiving paroxetine. Genotyping alone would not have predicted the low observed concentrations of endoxifen in this patient [113]. In another study of 97 patients on tamoxifen therapy, CYP2D6 phenotype (using dextromethorphan as the probe) showed a stronger association with plasma endoxifen concentrations than did CYP2D6 genotype.…”

Section: Addressing Phenoconversion In Future Studiesmentioning

confidence: 64%

Addressing phenoconversion: the Achilles' heel of personalized medicine

Shah

Smith

2015

Brit J Clinical Pharma

221

217

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Phenoconversion is a phenomenon that converts genotypic extensive metabolizers (EMs) into phenotypic poor metabolizers (PMs) of drugs, thereby modifying their clinical response to that of genotypic PMs. Phenoconversion, usually resulting from nongenetic extrinsic factors, has a significant impact on the analysis and interpretation of genotype-focused clinical outcome association studies and personalizing therapy in routine clinical practice. The high phenotypic variability or genotype-phenotype mismatch, frequently observed due to phenoconversion within the genotypic EM population, means that the real number of phenotypic PM subjects may be greater than predicted from their genotype alone, because many genotypic EMs would be phenotypically PMs. If the phenoconverted population with genotype-phenotype mismatch, most extensively studied for CYP2D6, is as large as the evidence suggests, there is a real risk that genotype-focused association studies, typically correlating only the genotype with clinical outcomes, may miss clinically strong pharmacogenetic associations, thus compromising any potential for advancing the prospects of personalized medicine. This review focuses primarily on co-medication-induced phenoconversion and discusses potential approaches to rectify some of the current shortcomings. It advocates routine phenotyping of subjects in genotype-focused association studies and proposes a new nomenclature to categorize study populations. Even with strong and reliable data associating patients' genotypes with clinical outcome(s), there are problems clinically in applying this knowledge into routine pharmacotherapy because of potential genotype-phenotype mismatch. Drug-induced phenoconversion during routine clinical practice remains a major public health issue. Therefore, the principal challenges facing personalized medicine, which need to be addressed, include identification of the following factors: (i) drugs that are susceptible to phenoconversion; (ii) co-medications that can cause phenoconversion; and (iii) dosage amendments that need to be applied during and following phenoconversion. Pharmacogenetics and personalized medicineThe majority of drug-metabolizing enzymes (DMEs) are subject to genetic polymorphism and show some degree of functionally significant polymorphism in the population. The clearest data in this regard relate to cytochromes P450 CYP2D6 and CYP2C19 and thiopurine methyltransferase (TPMT). These genetically determined polymorphisms give rise to three distinct genotype-based subpopulations with respect to each DME, namely extensive metabolizers (EMs), poor metabolizers (PMs) and a subgroup in between, the intermediate metabolizers (IMs). In addition, for CYP2D6 and CYP2C19, there is a fourth genotype, the ultrarapid metabolizer (UM) genotype, resulting from inheritance of either multiple copies of the functional wild-type allele, such as CYP2D6*1, or a higher metabolic capacity resulting from increased transcription of DME due to the presence of a genetic variant found in the promoter ...

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Section: Addressing Phenoconversion In Future Studiesmentioning

confidence: 64%

Addressing phenoconversion: the Achilles' heel of personalized medicine

Shah

Smith

2015

Brit J Clinical Pharma

221

217

View full text Add to dashboard Cite

show abstract

“…For instance, an approach using dextromethorphan as a probe drug for both CYP2D6 and CYP3A activity has been suggested as an alternative strategy. Dextromethorphan appeared to be a good phenotyping probe to predict endoxifen exposure [84]. By developing a population pharmacokinetic model for tamoxifen, it was found that 54% of the variability in endoxifen exposure could be explained by dextromethorphan derived CYP2D6 and CYP3A4 phenotypes [85].…”

Section: Strategies To Individualize Tamoxifen Therapy: Phenotyping Amentioning

confidence: 99%

Individualization of tamoxifen therapy: Much more than just CYP2D6 genotyping

Binkhorst

Mathijssen

Jager

et al. 2015

Cancer Treatment Reviews

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101

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“…Based on our analysis and results of recent work [42], DM phenotyping might provide a standardized tool to assess the CYP2D6 metabolic capacity, which may even better predict the tamoxifen efficacy and endoxifen formation than extensive CYP2D6 genotyping.…”

Section: Discussionmentioning

confidence: 88%

The Discriminatory Value of <i>CYP2D6</i> Genotyping in Predicting the Dextromethorphan/Dextrorphan Phenotype in Women with Breast Cancer

et al. 2012

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Background: The growth inhibitory effect of tamoxifen is used for the treatment of breast cancer. Tamoxifen efficacy is mediated by its biotransformation, predominantly via the cytochrome P450 2D6 (CYP2D6) isoenzyme, to the active metabolite endoxifen. We investigated the relationship of CYP2D6 genotypes to the metabolism of dextromethorphan (DM), which is frequently used as a surrogate marker for the formation of endoxifen. Methods: The CYP2D6 genotype was determined by polymerase chain reaction (PCR) in previously untreated patients with hormone receptor-positive invasive breast cancer considered to receive antihormonal therapy. The DM/dextrorphan (DX) urinary excretion ratios were obtained in a subset of patients by high-pressure liquid chromatography (HPLC)-mediated urine analysis after intake of 25 mg DM. The relationships of genotype and corresponding phenotype were statistically analyzed for association. Results: From 151 patients predicted based on their genotype data for the ‘traditional’ CYP2D6 phenotype classes poor, intermediate, extensive and ultrarapid, 83 patients were examined for their DM/DX urinary ratios. The genotype-based poor metabolizer status correlated with the DM/DX ratios, whereas the intermediate, extensive and ultrarapid genotypes could not be distinguished based on their phenotype. Citalopram intake did not significantly influence the phenotype. Conclusions: The DM metabolism can be reliably used to assess the CYP2D6 enzyme activity. The correlation with the genotype can be incomplete and the metabolic ratios do not seem to be compromised by citalopram. DM phenotyping may provide a standardized tool to better assess the CYP2D6 metabolic capacity.

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Dextromethorphan As a Phenotyping Test to Predict Endoxifen Exposure in Patients on Tamoxifen Treatment

Cited by 49 publications

References 44 publications

Addressing phenoconversion: the Achilles' heel of personalized medicine

Addressing phenoconversion: the Achilles' heel of personalized medicine

Individualization of tamoxifen therapy: Much more than just CYP2D6 genotyping

The Discriminatory Value of <i>CYP2D6</i> Genotyping in Predicting the Dextromethorphan/Dextrorphan Phenotype in Women with Breast Cancer

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