Effects of CYP2D6 and CYP3A5 polymorphisms on tamoxifen and its metabolites in Thai breast cancer patients

Wanaporn Charoenchokthavee,1 Nutthada Areepium,2 Duangchit Panomvana,2 Virote Sriuranpong2 1Department of Pharmacy Practice, Faculty of Pharmaceutical Science, Chulalongkorn University, 2Medical Oncology Unit, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Pathumwan, Bangkok,...

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Autores principales:	Charoenchokthavee W, Areepium N, Panomvana D, Sriuranpong V
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2017
Materias:	Breast cancer tamoxifen endoxifen CYP2D6 CYP3A5 Thai Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/d0364aaba98542d18bb14c266e0b0865
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spelling	oai:doaj.org-article:d0364aaba98542d18bb14c266e0b08652021-12-02T02:51:13ZEffects of CYP2D6 and CYP3A5 polymorphisms on tamoxifen and its metabolites in Thai breast cancer patients1179-1314https://doaj.org/article/d0364aaba98542d18bb14c266e0b08652017-04-01T00:00:00Zhttps://www.dovepress.com/effects-of-cyp2d6-and-cyp3a5-polymorphisms-on-tamoxifen-and-its-metabo-peer-reviewed-article-BCTThttps://doaj.org/toc/1179-1314Wanaporn Charoenchokthavee,1 Nutthada Areepium,2 Duangchit Panomvana,2 Virote Sriuranpong2 1Department of Pharmacy Practice, Faculty of Pharmaceutical Science, Chulalongkorn University, 2Medical Oncology Unit, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Pathumwan, Bangkok, Thailand Purpose: This study aimed to determine the effects of CYP2D6 and CYP3A5 polymorphisms on the levels of tamoxifen (TAM) and its metabolites in the plasma of breast cancer patients. The protocol was designed to test the associations between CYP2D6, CYP3A5 genotypes and phenotypes (extensive metabolizer [EM], intermediate metabolizer [IM] and poor metabolizer [PM]) and TAM, N-desmethyl tamoxifen (NDMT), endoxifen (END) and 4-hydroxytamoxifen (4OHT) concentrations.Patients and methods: One hundred and thirty-four Thai breast cancer patients from the Thai Tamoxifen Project undergoing TAM treatment who met the inclusion/exclusion criteria were recruited. Plasma samples were assessed for the concentrations of TAM and its metabolites using high-performance liquid chromatography. The data are presented as actual values and metabolic ratios (MR). The hypotheses were tested using Kruskal–Wallis or Mann–Whitney U test, including the simple main effects analysis.Results: The patients had stage 0–IV breast cancer. The mean age and body mass index were 51.6±11.6 years and 24.0±4.3, respectively. Also, 53.0% of them were premenopausal, 10.4% were perimenopausal and 36.6% were postmenopausal, while 23.1% were CYP2D6-EM/CYP3A5-EM and 20.9% carried only CYP2D6 and CYP3A5 incomplete alleles. The median concentrations of TAM, NDMT, END and 4OHT were 374.7 (interquartile range [IQR] 230.2) ng/mL, 1,064.9 (IQR 599.6) ng/mL, 54.5 (IQR 52.5) ng/mL and 5.0 (IQR 3.1) ng/mL, respectively. MR (TAM-NDMT) and MR (NDMT-END) were statistically different (p=0.013 and p=0.014, respectively), while MR (4OHT-END) was not statistically different within the CYP2D6 phenotype (p=0.594). MR (TAM-4OHT) was not statistically different within the CYP2D6 phenotype (p=0.079), but it was potentially different from CYP3A5-PM (p=0.056). None of the MR was statistically different within the CYP3A5 phenotype.Conclusion: CYP2D6 polymorphisms appear to affect END concentration through an NDMT subpathway and potentially affect 4OHT concentrations through a 4OHT subpathway in CYP3A5-PM group. Keywords: endoxifen, cytochrome P450, single nucleotide polymorphisms, pharmacogenetics, pharmacogenomics, humanCharoenchokthavee WAreepium NPanomvana DSriuranpong VDove Medical PressarticleBreast cancertamoxifenendoxifenCYP2D6CYP3A5ThaiNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENBreast Cancer: Targets and Therapy, Vol Volume 9, Pp 249-256 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Breast cancer tamoxifen endoxifen CYP2D6 CYP3A5 Thai Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Breast cancer tamoxifen endoxifen CYP2D6 CYP3A5 Thai Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Charoenchokthavee W Areepium N Panomvana D Sriuranpong V Effects of CYP2D6 and CYP3A5 polymorphisms on tamoxifen and its metabolites in Thai breast cancer patients
description	Wanaporn Charoenchokthavee,1 Nutthada Areepium,2 Duangchit Panomvana,2 Virote Sriuranpong2 1Department of Pharmacy Practice, Faculty of Pharmaceutical Science, Chulalongkorn University, 2Medical Oncology Unit, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Pathumwan, Bangkok, Thailand Purpose: This study aimed to determine the effects of CYP2D6 and CYP3A5 polymorphisms on the levels of tamoxifen (TAM) and its metabolites in the plasma of breast cancer patients. The protocol was designed to test the associations between CYP2D6, CYP3A5 genotypes and phenotypes (extensive metabolizer [EM], intermediate metabolizer [IM] and poor metabolizer [PM]) and TAM, N-desmethyl tamoxifen (NDMT), endoxifen (END) and 4-hydroxytamoxifen (4OHT) concentrations.Patients and methods: One hundred and thirty-four Thai breast cancer patients from the Thai Tamoxifen Project undergoing TAM treatment who met the inclusion/exclusion criteria were recruited. Plasma samples were assessed for the concentrations of TAM and its metabolites using high-performance liquid chromatography. The data are presented as actual values and metabolic ratios (MR). The hypotheses were tested using Kruskal–Wallis or Mann–Whitney U test, including the simple main effects analysis.Results: The patients had stage 0–IV breast cancer. The mean age and body mass index were 51.6±11.6 years and 24.0±4.3, respectively. Also, 53.0% of them were premenopausal, 10.4% were perimenopausal and 36.6% were postmenopausal, while 23.1% were CYP2D6-EM/CYP3A5-EM and 20.9% carried only CYP2D6 and CYP3A5 incomplete alleles. The median concentrations of TAM, NDMT, END and 4OHT were 374.7 (interquartile range [IQR] 230.2) ng/mL, 1,064.9 (IQR 599.6) ng/mL, 54.5 (IQR 52.5) ng/mL and 5.0 (IQR 3.1) ng/mL, respectively. MR (TAM-NDMT) and MR (NDMT-END) were statistically different (p=0.013 and p=0.014, respectively), while MR (4OHT-END) was not statistically different within the CYP2D6 phenotype (p=0.594). MR (TAM-4OHT) was not statistically different within the CYP2D6 phenotype (p=0.079), but it was potentially different from CYP3A5-PM (p=0.056). None of the MR was statistically different within the CYP3A5 phenotype.Conclusion: CYP2D6 polymorphisms appear to affect END concentration through an NDMT subpathway and potentially affect 4OHT concentrations through a 4OHT subpathway in CYP3A5-PM group. Keywords: endoxifen, cytochrome P450, single nucleotide polymorphisms, pharmacogenetics, pharmacogenomics, human
format	article
author	Charoenchokthavee W Areepium N Panomvana D Sriuranpong V
author_facet	Charoenchokthavee W Areepium N Panomvana D Sriuranpong V
author_sort	Charoenchokthavee W
title	Effects of CYP2D6 and CYP3A5 polymorphisms on tamoxifen and its metabolites in Thai breast cancer patients
title_short	Effects of CYP2D6 and CYP3A5 polymorphisms on tamoxifen and its metabolites in Thai breast cancer patients
title_full	Effects of CYP2D6 and CYP3A5 polymorphisms on tamoxifen and its metabolites in Thai breast cancer patients
title_fullStr	Effects of CYP2D6 and CYP3A5 polymorphisms on tamoxifen and its metabolites in Thai breast cancer patients
title_full_unstemmed	Effects of CYP2D6 and CYP3A5 polymorphisms on tamoxifen and its metabolites in Thai breast cancer patients
title_sort	effects of cyp2d6 and cyp3a5 polymorphisms on tamoxifen and its metabolites in thai breast cancer patients
publisher	Dove Medical Press
publishDate	2017
url	https://doaj.org/article/d0364aaba98542d18bb14c266e0b0865
work_keys_str_mv	AT charoenchokthaveew effectsofcyp2d6andcyp3a5polymorphismsontamoxifenanditsmetabolitesinthaibreastcancerpatients AT areepiumn effectsofcyp2d6andcyp3a5polymorphismsontamoxifenanditsmetabolitesinthaibreastcancerpatients AT panomvanad effectsofcyp2d6andcyp3a5polymorphismsontamoxifenanditsmetabolitesinthaibreastcancerpatients AT sriuranpongv effectsofcyp2d6andcyp3a5polymorphismsontamoxifenanditsmetabolitesinthaibreastcancerpatients
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Effects of CYP2D6 and CYP3A5 polymorphisms on tamoxifen and its metabolites in Thai breast cancer patients

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