Login Register Cart 0
Generic placeholder image

Current Pharmacogenomics and Personalized Medicine

Editor-in-Chief

ISSN (Print): 1875-6921
ISSN (Online): 1875-6913

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Factors Associated with Plasma Levels of Tamoxifen and its Main Metabolites in Mexican Patients with Breast Cancer

Author(s): Miriam Morales, Silvia Romano*, Angélica Aguilar, Susanna Medellín, Rosa Milán, José Cruz, José Zermeño and Alejandra Segarra

Volume 19, Issue 2, 2022

Published on: 26 September, 2022

Page: [86 - 99] Pages: 14

DOI: 10.2174/1875692119666220830100021

Price: $65

Abstract

Background: Tamoxifen (TAM) is commonly prescribed as adjuvant therapy in women with estrogen receptor-positive breast cancer. Unfortunately, not all patients respond adequately to this drug. This variation in pharmacological response has been associated with different factors, including genetic polymorphisms of enzymes responsible for the metabolism of TAM.

Objective: To determine the concentrations of tamoxifen (TAM) and its main metabolites in Mexican women with breast cancer and to evaluate its relationship with genetic, demographic and anthropometric characteristics.

Methods: Eighty-four patients with a mean age of 49.3 (± 8.8) years were included in the study. Plasma concentrations of TAM and its metabolites N-desmethyl-tamoxifen (NDT), 4- hydroxy-tamoxifen (4HT) and endoxifen (END) were determined in predose for each patient. CYP2D6 * 4, * 10 and CYP3A5 * 3 genetic polymorphisms were characterized. Demographic, anthropometric, biochemical and clinical data were recorded for each patient.

Results: Plasma concentrations of 4HT and END were higher in the extensive metabolizer (EM) phenotype than in the intermediate metabolizer (IM) phenotype (p<0.05). The metabolic ratio (MR) [END+4HT]/[TAM+NDT] was lower in patients with the CYP2D6 IM phenotype than those with the EM phenotype (p= 0.014). Regarding anthropometric factors, a positive correlation was found for 4HT and the END concerning age (R = 0.256 and 0.232, respectively). The body mass index (BMI) presented a statistically significant correlation with the concentrations of NDT (R=-0.351) and 4HT (R=-0.298).

Conclusion: CYP2D6 phenotype, age and BMI could help to explain part of the interindividual variability of TAM plasma levels and its metabolites in the Mexican population.

Keywords: Tamoxifen, endoxifen, age, body mass index, CYP2D6, breast cancer.

« Previous
Graphical Abstract

[1]
Gradishar, W.; Salerno, K.E. NCCN Guidelines update: Breast cancer. J. Natl. Compr. Canc. Netw., 2016, 14(5S), 641-644.
[http://dx.doi.org/10.6004/jnccn.2016.0181] [PMID: 27226503]
[2]
Pan, H.; Gray, R.; Braybrooke, J.; Davies, C.; Taylor, C.; McGale, P.; Peto, R.; Pritchard, K.I.; Bergh, J.; Dowsett, M.; Hayes, D.F. 20 Year risks of breast cancer recurrence after stopping endocrine therapy at 5 years. N. Engl. J. Med., 2017, 377(19), 1836-1846.
[http://dx.doi.org/10.1056/NEJMoa1701830] [PMID: 29117498]
[3]
Hwang, G.S.; Bhat, R.; Crutchley, R.D.; Trivedi, M.V. Impact of CYP2D6 polymorphisms on endoxifen concentrations and breast cancer outcomes. Pharmacogenomics J., 2018, 18(2), 201-208.
[http://dx.doi.org/10.1038/tpj.2017.36] [PMID: 28762370]
[4]
Saladores, P.; MA1/4rdter, T.; Eccles, D.; Chowbay, B.; Zgheib, N.K.; Winter, S.; Ganchev, B.; Eccles, B.; Gerty, S.; Tfayli, A.; Lim, J.S.L.; Yap, Y.S.; Ng, R.C.H.; Wong, N.S.; Dent, R.; Habbal, M.Z.; Schaeffeler, E.; Eichelbaum, M.; Schroth, W.; Schwab, M.; Brauch, H. Tamoxifen metabolism predicts drug concentrations and outcome in premenopausal patients with early breast cancer. Pharmacogenomics J., 2015, 15(1), 84-94.
[http://dx.doi.org/10.1038/tpj.2014.34] [PMID: 25091503]
[5]
Teft, W.A.; Gong, I.Y.; Dingle, B.; Potvin, K.; Younus, J.; Vandenberg, T.A.; Brackstone, M.; Perera, F.E.; Choi, Y.H.; Zou, G.; Legan, R.M.; Tirona, R.G.; Kim, R.B. CYP3A4 and seasonal variation in vitamin D status in addition to CYP2D6 contribute to therapeutic endoxifen level during tamoxifen therapy. Breast Cancer Res. Treat., 2013, 139(1), 95-105.
[http://dx.doi.org/10.1007/s10549-013-2511-4] [PMID: 23580071]
[6]
Madlensky, L.; Natarajan, L.; Tchu, S.; Pu, M.; Mortimer, J.; Flatt, S.W.; Nikoloff, D.M.; Hillman, G.; Fontecha, M.R.; Lawrence, H.J.; Parker, B.A.; Wu, A.H.B.; Pierce, J.P. Tamoxifen metabolite concentrations, CYP2D6 genotype, and breast cancer outcomes. Clin. Pharmacol. Ther., 2011, 89(5), 718-725.
[http://dx.doi.org/10.1038/clpt.2011.32] [PMID: 21430657]
[7]
Vries, S.A.H.M.; Zwart, W.; Linn, S.C.; Beijnen, J.H.; Huitema, A.D.R. Effects of pharmacogenetics on the pharmacokinetics and pharmacodynamics of tamoxifen. Clin. Pharmacokinet., 2015, 54(8), 797-810.
[http://dx.doi.org/10.1007/s40262-015-0273-3] [PMID: 25940823]
[8]
Binkhorst, L.; Mathijssen, R.H.J.; Jager, A.; Gelder, T. Individualization of tamoxifen therapy: Much more than just CYP2D6 genotyping. Cancer Treat. Rev., 2015, 41(3), 289-299.
[http://dx.doi.org/10.1016/j.ctrv.2015.01.002] [PMID: 25618289]
[9]
Bradford, L.D. CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics, 2002, 3(2), 229-243.
[http://dx.doi.org/10.1517/14622416.3.2.229] [PMID: 11972444]
[10]
Sanchez, S.A.B.; Swen, J.J.; Dezentje, V.O.; Moes, D.J.A.R.; Gelderblom, H.; Guchelaar, H.J. Clinical pharmacokinetics and pharmacogenetics of tamoxifen and endoxifen. Expert Rev. Clin. Pharmacol., 2019, 12(6), 523-536.
[http://dx.doi.org/10.1080/17512433.2019.1610390] [PMID: 31008668]
[11]
Ahmed, J.H.; Makonnen, E.; Fotoohi, A.; Aseffa, A.; Howe, R.; Aklillu, E. CYP2D6 genotype predicts plasma concentrations of tamoxifen metabolites in ethiopian breast cancer patients. Cancers, 2019, 11(9), 1353.
[http://dx.doi.org/10.3390/cancers11091353] [PMID: 31547390]
[12]
Jin, Y.; Desta, Z.; Stearns, V.; Ward, B.; Ho, H.; Lee, K.H.; Skaar, T.; Storniolo, A.M.; Li, L.; Araba, A.; Blanchard, R.; Nguyen, A.; Ullmer, L.; Hayden, J.; Lemler, S.; Weinshilboum, R.M.; Rae, J.M.; Hayes, D.F.; Flockhart, D.A. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J. Natl. Cancer Inst., 2005, 97(1), 30-39.
[http://dx.doi.org/10.1093/jnci/dji005] [PMID: 15632378]
[13]
Lien, E.A.; Sailand, H.; Lundgren, S.; Aas, T.; Steen, V.M.; Mellgren, G.; Gjerde, J. Serum concentrations of tamoxifen and its metabolites increase with age during steady state treatment. Breast Cancer Res. Treat., 2013, 141(2), 243-248.
[http://dx.doi.org/10.1007/s10549-013-2677-9] [PMID: 23996142]
[14]
Sheth, H.R.; Lord, G.; Tkaczuk, K.; Danton, M.; Lewis, L.M.; Langenberg, P.; Lim, C.K.; Flaws, J.A. Aging may be associated with concentrations of tamoxifen and its metabolites in breast cancer patients. J. Womens Health, 2003, 12(8), 799-808.
[http://dx.doi.org/10.1089/154099903322447765] [PMID: 14588130]
[15]
Schultink, A.H.M.; Huitema, A.D.R.; Beijnen, J.H. Therapeutic drug monitoring of endoxifen as an alternative for CYP2D6 genotyping in individualizing tamoxifen therapy. Breast, 2018, 42, 38-40.
[http://dx.doi.org/10.1016/j.breast.2018.08.100] [PMID: 30153552]
[16]
Antunes, M.V.; Linden, R.; Santos, T.V.; Wallemacq, P.; Haufroid, V.; Classen, J.F.; Andreolla, H.; Costa, N.; Fontanive, T.O.; Rosa, D.D. Endoxifen levels and its association with CYP2D6 genotype and phenotype: Evaluation of a southern Brazilian population under tamoxifen pharmacotherapy. Ther. Drug Monit., 2012, 34(4), 422-431.
[http://dx.doi.org/10.1097/FTD.0b013e318260b46e] [PMID: 22777153]
[17]
Caudle, K.E.; Sangkuhl, K.; Whirl, C.M.; Swen, J.J.; Haidar, C.E.; Klein, T.E.; Gammal, R.S.; Relling, M.V.; Scott, S.A.; Hertz, D.L.; Guchelaar, H.J.; Gaedigk, A. Standardizing CYP 2D6 genotype to phenotype translation: Consensus recommendations from the clinical pharmacogenetics implementation consortium and dutch pharmacogenetics working group. Clin. Transl. Sci., 2020, 13(1), 116-124.
[http://dx.doi.org/10.1111/cts.12692] [PMID: 31647186]
[18]
Sol, A.; (c), X.; GuinA3, E.; Valls, J.; Iniesta, R.; Moreno, V. SNPStats: A web tool for the analysis of association studies. Bioinformatics, 2006, 22(15), 1928-1929.
[http://dx.doi.org/10.1093/bioinformatics/btl268] [PMID: 16720584]
[19]
Tchu, S.M.; Lynch, K.L.; Wu, A.H.B. Therapeutic drug monitoring of tamoxifen using LC-MS/MS. Methods Mol. Biol., 2012, 902, 211-222.
[http://dx.doi.org/10.1007/978-1-61779-934-1_19] [PMID: 22767121]
[20]
Love, R.R.; Desta, Z.; Flockhart, D.; Skaar, T.; Ogburn, E.T.; Ramamoorthy, A.; Uy, G.B.; Laudico, A.V.; Van, D.N.; Quang, L.H.; Van To, T.; Young, G.S.; Hade, E.; Jarjoura, D. CYP2D6 genotypes, endoxifen levels, and disease recurrence in 224 Filipino and Vietnamese women receiving adjuvant tamoxifen for operable breast cancer. Springerplus, 2013, 2(1), 52.
[http://dx.doi.org/10.1186/2193-1801-2-52] [PMID: 23476897]
[21]
Lei, L.; Wang, X.; Wu, X.D.; Wang, Z.; Chen, Z.H.; Zheng, Y.B.; Wang, X.J. Association of CYP2D6*10 (c.100C>T) polymorphisms with clinical outcome of breast cancer after tamoxifen adjuvant endocrine therapy in Chinese population. Am. J. Transl. Res., 2016, 8(8), 3585-3592.
[PMID: 27648149]
[22]
Rangel, M.; J.A.; Graniel, S.M.J.; Sanchez, C.J.F.; Moo, P.R. Development of a high-performance liquid chromatography method with fluorescence detection for the routine quantification of tamoxifen, endoxifen and 4-hydroxytamoxifen in plasma from breast cancer patients. Biomed. Chromatogr., 2019, 33(4), e4462.
[PMID: 30536934]
[23]
Wang, D.; Jiang, Z.; Shen, Z.; Wang, H.; Wang, B.; Shou, W.; Zheng, H.; Chu, X.; Shi, J.; Huang, W. Functional evaluation of genetic and environmental regulators of p450 mRNA levels. PLoS One, 2011, 6(10), e24900.
[http://dx.doi.org/10.1371/journal.pone.0024900] [PMID: 21998633]
[24]
Lazalde, R.B.P.; Marta, F.M.L.; Galaviz, H.C.; Garza, V.I.; Naranjo, M.E.G.; Sosa, M.M.; Llerena, A. CYP2D6 gene polymorphisms and predicted phenotypes in eight indigenous groups from northwestern Mexico. Pharmacogenomics, 2014, 15(3), 339-348.
[http://dx.doi.org/10.2217/pgs.13.203] [PMID: 24533713]
[25]
Jorge, A.R.M.; Rodrigo, R.C.; Esther, M.P.R. Endoxifen levels and metabolic phenotype-associated factors in Mexican Mestizo patients under tamoxifen treatment. Pharmacogenomics, 2020, 21(13), 929-943.
[http://dx.doi.org/10.2217/pgs-2020-0061] [PMID: 32808577]
[26]
Salazar, F.J.; Torres, R.L.A.; Marta, C.G.; Rubi, C.R.; Sosa, M.M.; Muaoz, V.J.F.; Gonzalez, G.C.; Rama, A.; Roman, R.; Macndez, J.L.; Barrera, A.; Torres, A.; Medina, R.; Rangel, V.H. Distribution of CYP2D6 and CYP2C19 polymorphisms associated with poor metabolizer phenotype in five Amerindian groups and western Mestizos from Mexico. Genet. Test. Mol. Biomarkers, 2012, 16(9), 1098-1104.
[http://dx.doi.org/10.1089/gtmb.2012.0055] [PMID: 22913530]
[27]
Galaviz, H.C.; Lazalde, R.B.P.; Lares, A.I.; Maca, S.A.; Ortega, C.M.A.; Rangel, V.H.; Sosa, M.M. Influence of genetic admixture components on CYP3A5*3 allele-associated hypertension in amerindian populations from northwest Mexico. Front. Pharmacol., 2020, 11, 638.
[http://dx.doi.org/10.3389/fphar.2020.00638] [PMID: 32477124]
[28]
Garca, R.P.; Medeiros, M.; Reyes, H.; Rodra, E.B.A.; Albera, J.; Ortiz, L.; Vasquez, P.M.; Elizondo, G.; Morales, B.L.E.; Mancilla, U.E.; Castaaeda, H.G. CYP3A5 polymorphism in Mexican renal transplant recipients and its association with tacrolimus dosing. Arch. Med. Res., 2012, 43(4), 283-287.
[http://dx.doi.org/10.1016/j.arcmed.2012.05.005] [PMID: 22704849]
[29]
MA1/4rdter, T.E.; Schroth, W.; Bacchus, G.L.; Winter, S.; Heinkele, G.; Simon, W.; Fasching, P.A.; Fehm, T.; Eichelbaum, M.; Schwab, M.; Brauch, H. Activity levels of tamoxifen metabolites at the estrogen receptor and the impact of genetic polymorphisms of phase I and II enzymes on their concentration levels in plasma. Clin. Pharmacol. Ther., 2011, 89(5), 708-717.
[http://dx.doi.org/10.1038/clpt.2011.27] [PMID: 21451508]
[30]
Schroth, W.; Winter, S.; MA1/4rdter, T.; Schaeffeler, E.; Eccles, D.; Eccles, B.; Chowbay, B.; Khor, C.C.; Tfayli, A.; Zgheib, N.K.; Eichelbaum, M.; Schwab, M.; Brauch, H. Improved prediction of endoxifen metabolism by cyp2d6 genotype in breast cancer patients treated with tamoxifen. Front. Pharmacol., 2017, 8, 582.
[http://dx.doi.org/10.3389/fphar.2017.00582] [PMID: 28955222]
[31]
Puszkiel, A.; Arellano, C.; Vachoux, C.; Evrard, A.; Le Morvan, V.; Boyer, J.C.; Robert, J.; Delmas, C.; Dalenc, F.; Debled, M.; Venat, B.L.; Jacot, W.; Suc, E.; Sillet, B.I.; Filleron, T.; Rocha, H.; Chatelut, E.; White, K.M.; Thomas, F. Factors affecting tamoxifen metabolism in patients with breast cancer: Preliminary results of the french PHACS study. Clin. Pharmacol. Ther., 2019, 106(3), 585-595.
[http://dx.doi.org/10.1002/cpt.1404] [PMID: 30786012]
[32]
Wu, A.H.B.; Lorizio, W.; Tchu, S.; Lynch, K.; Gerona, R.; Ji, W.; Ruan, W.; Ruddy, K.J.; Desantis, S.D.; Burstein, H.J.; Ziv, E. Estimation of tamoxifen metabolite concentrations in the blood of breast cancer patients through CYP2D6 genotype activity score. Breast Cancer Res. Treat., 2012, 133(2), 677-683.
[http://dx.doi.org/10.1007/s10549-012-1963-2] [PMID: 22294487]
[33]
Woo, H.I.; Lee, S.K.; Kim, J.; Kim, S.W.; Yu, J.; Bae, S.Y.; Lee, J.E.; Nam, S.J.; Lee, S.Y. Variations in plasma concentrations of tamoxifen metabolites and the effects of genetic polymorphisms on tamoxifen metabolism in Korean patients with breast cancer. Oncotarget, 2017, 8(59), 100296-100311.
[http://dx.doi.org/10.18632/oncotarget.22220] [PMID: 29245979]
[34]
Peyrade, F.; Frenay, M.; Etienne, M.C.; Ruch, F.; Guillemare, C.; Franois, E.; Namer, M.; Ferrero, J.M.; Milano, G. Age related difference in tamoxifen disposition. Clin. Pharmacol. Ther., 1996, 59(4), 401-410.
[http://dx.doi.org/10.1016/S0009-9236(96)90108-3] [PMID: 8612384]
[35]
Wu, A.H.; Pike, M.C.; Williams, L.D.; Spicer, D.; Tseng, C.C.; Churchwell, M.I.; Doerge, D.R. Tamoxifen, soy, and lifestyle factors in Asian American women with breast cancer. J. Clin. Oncol., 2007, 25(21), 3024-3030.
[http://dx.doi.org/10.1200/JCO.2006.10.5023] [PMID: 17536081]
[36]
Pączek, B.C.; Mucha, K.; Pączek, L. Age related decline in renal blood flow could be a beneficial and compensatory mechanism. Med. Sci. Monit., 2020, 26, e918643.
[http://dx.doi.org/10.12659/MSM.918643] [PMID: 32015299]
[37]
Mangoni, A.A.; Jackson, S.H.D. Age related changes in pharmacokinetics and pharmacodynamics: Basic principles and practical applications. Br. J. Clin. Pharmacol., 2004, 57(1), 6-14.
[http://dx.doi.org/10.1046/j.1365-2125.2003.02007.x] [PMID: 14678335]
[38]
Antunes, M.V.; Fontoura, T.T.A.; Oliveira, V.; Staudt, D.E.; Raymundo, S.; Gssling, G.; Biazs, J.V.; Cavalheiro, J.A.; Rosa, D.D.; Wallemacq, P.; Haufroid, V.; Linden, R.; Schwartsmann, G. Influence of CYP2D6 and CYP3A4 phenotypes, drug interactions, and vitamin D status on tamoxifen biotransformation. Ther. Drug Monit., 2015, 37(6), 733-744.
[http://dx.doi.org/10.1097/FTD.0000000000000212] [PMID: 25853922]
[39]
Tamoxifen. National Center for Biotechnology Information. PubChem Compound Summary for CID 2733526, Tamoxifen., Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Tamoxifen (Accessed on: Mar 12, 2021).
[40]
Endoxifen. National Center for Biotechnology Information. PubChem Compound Summary for CID 10090750, Endoxifen., Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Endoxifen (Accessed on: Mar 12, 2021).
[41]
N-Desmethyltamoxifen. National Center for Biotechnology Information. PubChem Compound Summary for CID 6378383, N-desmethyltamoxifen., Available from: https://pubchem.ncbi.nlm.nih.gov/compound/N-Desmethyltamoxifen (Accessed on: Mar 12, 2021).
[42]
4-Hydroxytamoxifen. National Center for Biotechnology Information. PubChem Compound Summary for CID 449459, 4-Hydroxytamoxifen., Available from: https://pubchem.ncbi.nlm.nih.gov/compound/4-Hydroxytamoxifen (Accessed on: Mar 12, 2021).
[43]
Mansoor, A.; Mahabadi, N. Volume of Distribution; StatPearls, 2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK545280/ (Accessed on: Mar 18, 2021).
[44]
Bourassa, P.; Dubeau, S.; Maharvi, G.M.; Fauq, A.H.; Thomas, T.J.; Tajmir, R.H.A. Binding of antitumor tamoxifen and its metabolites 4-hydroxytamoxifen and endoxifen to human serum albumin. Biochimie, 2011, 93(7), 1089-1101.
[http://dx.doi.org/10.1016/j.biochi.2011.03.006] [PMID: 21439346]
[45]
Cuautle, R.P.; Llerena, A.; Molina, G.J. Present status and perspective of pharmacogenetics in Mexico. Drug Metabol. Drug Interact., 2014, 29(1), 37-45.
[http://dx.doi.org/10.1515/dmdi-2013-0019] [PMID: 24129103]
[46]
Khalaj, Z.; Baratieh, Z.; Nikpour, P.; Schwab, M.; Schaeffeler, E.; Mokarian, F.; Khanahmad, H.; Salehi, R.; MA1/4rdter, T.E.; Salehi, M. Clinical trial: CYP2D6 related dose escalation of tamoxifen in breast cancer patients with Iranian ethnic background resulted in increased concentrations of tamoxifen and its metabolites. Front. Pharmacol., 2019, 10, 530.
[http://dx.doi.org/10.3389/fphar.2019.00530] [PMID: 31178724]
[47]
Hennig, E.E.; Piatkowska, M.; Karczmarski, J.; Goryca, K.; Brewczynska, E.; Jazwiec, R.; Kluska, A.; Omiotek, R.; Paziewska, A.; Dadlez, M.; Ostrowski, J. Limited predictive value of achieving beneficial plasma (Z)-endoxifen threshold level by CYP2D6 genotyping in tamoxifen treated polish women with breast cancer. BMC Cancer, 2015, 15(1), 570.
[http://dx.doi.org/10.1186/s12885-015-1575-4] [PMID: 26232141]
[48]
Heery, M.; Corbett, P.; Zelkowitz, R. Precautions for patients taking tamoxifen. J. Adv. Pract. Oncol., 2018, 9(1), 78-83.
[PMID: 30564470]

Rights & Permissions Print Cite
Article Metrics
1
© 2024 Bentham Science Publishers | Privacy Policy