Effects of Genetic Polymorphisms of Drug Metabolizing Enzymes and co‐Medications on Tamoxifen Metabolism in Black South African Women with Breast Cancer

Chiwambutsa, Shingirai; Ayeni, Oluwatosin; Kapungu, Nyasha; Kanji, Comfort; Thelingwani, Roslyn; Chen, Wenlong Carl; Mokone, D; O’Neil, Daniel S.; Neugut, Alfred I.; Jacobson, Judith S.; Ruff, Paul; Cubasch, Herbert; Joffe, Maureen; Masimirembwa, Collen

doi:10.1002/cpt.2904

Cited by 3 publications

(4 citation statements)

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“…33 The activity of CYP2D6*29 is comparable to that of CYP2D6*17 in the metabolism of NDMtamoxifen to endoxifen in vitro 34 and in breast cancer patients. 35 Both CYP2D6*17 and *29 have higher activity compared to CYP2D6*10. 34 Taking into account Kanji's findings that estimated the AS of CYP2D6*17 to be 0.3 36 and the revised AS of CYP2D6*10 of 0.25, 37 we therefore expect the CYP2D6*19 AS to be around that of CYP2D6*17, of 0.30.…”

Section: Discussionmentioning

confidence: 98%

“…This could be achieved with CYP2D6*17 as the two enzymes have been shown to have comparable activity in vitro 33 . The activity of CYP2D6*29 is comparable to that of CYP2D6*17 in the metabolism of NDM‐tamoxifen to endoxifen in vitro 34 and in breast cancer patients 35 . Both CYP2D6*17 and *29 have higher activity compared to CYP2D6*10 34 .…”

Section: Discussionmentioning

confidence: 99%

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Pharmacogenetics and pharmacokinetics of tamoxifen in a Zimbabwean breast cancer cohort

Mbavha

Thelingwani

Chikwambi

et al. 2023

Brit J Clinical Pharma

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Tamoxifen is the most used hormonal therapy for oestrogen receptor‐positive breast cancer. CYP2D6 is the main enzyme in the metabolic pathway of tamoxifen to endoxifen. Variations in endoxifen plasma concentrations are associated with CYP2D6 polymorphisms. This study aimed to determine the association between the CYP2D6 polymorphisms and endoxifen plasma concentrations in a cohort of Zimbabwean breast cancer patients (n = 40). TaqMan genotyping and copy number assays were done to determine CYP2D6 genotypes. Tamoxifen and metabolites were quantitated using LC‐MS/MS. The population had high frequencies of the CYP2D6 reduced function alleles, *17 (15%) and *29 (18%). The median endoxifen concentration was 4.78 ng/mL, and in 55% of the patients, mostly intermediate metabolizers were below the endoxifen therapeutic threshold of 5.97 ng/mL. The CYP2D6 phenotypes and activity scores were significantly associated with endoxifen plasma concentrations (P = 0.0151) and with endoxifen to N‐desmethyl‐tamoxifen ratios (P = 0.0006).

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Pharmacogenetics and pharmacokinetics of tamoxifen in a Zimbabwean breast cancer cohort

Mbavha

Thelingwani

Chikwambi

et al. 2023

Brit J Clinical Pharma

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“…Significant effects of genetic polymorphisms of CYP2D6 and CYP3A4 enzymes have been observed to affect the metabolism of TMX and the concentrations of endoxifen. The most active metabolite is lowered with some polymorphisms which require dose adjustments , …”

Section: Characterizations Of Resistance Of Different Chemotherapy Dr...mentioning

confidence: 99%

“…192 Significant effects of genetic polymorphisms of CYP2D6 and CYP3A4 enzymes have been observed to affect the metabolism of TMX and the concentrations of endoxifen. The most active metabolite is lowered with some polymorphisms which require dose adjustments 193,194 13. CONCLUSION "Omic" data in any cancer is generated as a continuum representing the aberrant cellular activities rather than the "omic" terminologies on central dogma which restricts omic in terms of genomic, transcriptomic, proteomics, and metabolomic.…”

Section: Characterizations Of Resistance Of Different Chemotherapy Dr...mentioning

confidence: 99%

Recent Contributions of Mass Spectrometry-Based “Omics” in the Studies of Breast Cancer

Banerjee,

Hatimuria,

Sarkar

et al. 2023

Chem. Res. Toxicol.

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Breast cancer (BC) is one of the most heterogeneous groups of cancer. As every biotype of BC is unique and presents a particular "omic" signature, they are increasingly characterized nowadays with novel mass spectrometry (MS) strategies. BC therapeutic approaches are primarily based on the two features of human epidermal growth factor receptor 2 (HER2) and estrogen receptor (ER) positivity. Various strategic MS implementations are reported in studies of BC also involving data independent acquisitions (DIAs) of MS which report novel differential proteomic, lipidomic, proteogenomic, phosphoproteomic, and metabolomic characterizations associated with the disease and its therapeutics. Recently many "omic" studies have aimed to identify distinct subsidiary biotypes for diagnosis, prognosis, and targets of treatment. Along with these, drug-induced-resistance phenotypes are characterized by "omic" changes. These identifying aspects of the disease may influence treatment outcomes in the near future. Drug quantifications and characterizations are also done regularly and have implications in therapeutic monitoring and in drug efficacy assessments. We report these studies, mentioning their implications toward the understanding of BC. We briefly provide the MS instrumentation principles that are adopted in such studies as an overview with a brief outlook on DIA-MS strategies. In all of these, we have chosen a model cancer for its revelations through MS-based "omics".

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Population pharmacokinetic modeling of tamoxifen and its active metabolite endoxifen in healthy volunteers of African ancestry genotyped for CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and CYP3A5.

Chiwambutsa,

Ali,

Cubasch

et al. 2024

Preprint

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Purpose Wide inter-individual variability is seen in the clinical outcomes of tamoxifen treatment, which may be attributable to cytochrome P450 genetic polymorphisms. To investigate this, we analysed data from an open-label three parallel arm trial with 36 healthy volunteers of African ancestry to whom a dose of 20 mg of tamoxifen had been administered and drug concentrations of tamoxifen and its three metabolites measured over 34 time points after administration. Methods The data was best described by a pharmacokinetic model, which focused on tamoxifen and its active metabolite endoxifen only. The model was described by a two-compartment model for the parent linked to a one-compartment model for the metabolite. Results Data exploration and estimated pharmacokinetic parameters for both compounds indicated wide variability between participants. The findings demonstrated high inter individual variability (99.3%) in the formation of endoxifen with no evidence to suggest that the CYP2D6 gene could explain this variation. Model diagnostic plots such as goodness of fit plots and visual predictive checks showed a good predictive performance of the model. Conclusion Age, BMI, CYP2D6, CYP3A4, CYP3A5, CYP2B6, CYP2C9 and CYP2C19 genotypes had no significant impact in explaining the variability in pharmacokinetic parameters for tamoxifen and endoxifen.

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Effects of Genetic Polymorphisms of Drug Metabolizing Enzymes and co‐Medications on Tamoxifen Metabolism in Black South African Women with Breast Cancer

Cited by 3 publications

References 47 publications

Pharmacogenetics and pharmacokinetics of tamoxifen in a Zimbabwean breast cancer cohort

Pharmacogenetics and pharmacokinetics of tamoxifen in a Zimbabwean breast cancer cohort

Recent Contributions of Mass Spectrometry-Based “Omics” in the Studies of Breast Cancer

Population pharmacokinetic modeling of tamoxifen and its active metabolite endoxifen in healthy volunteers of African ancestry genotyped for CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and CYP3A5.

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