A pharmacogenetic pilot study reveals MTHFR, DRD3, and MDR1 polymorphisms as biomarker candidates for slow atorvastatin metabolizers

Rafael B.R. León-Cachón; Jorge A. Ascacio-Martínez; María E. Gamino-Peña; Ricardo M. Cerda-Flores; Irene Meester; Hugo L. Gallardo-Blanco; Magdalena Gómez-Silva; Everardo Piñeyro-Garza; Hugo A. Barrera-Saldaña

doi:10.1186/s12885-016-2062-2

A pharmacogenetic pilot study reveals MTHFR, DRD3, and MDR1 polymorphisms as biomarker candidates for slow atorvastatin metabolizers

Rafael B.R. León-Cachón, Jorge A. Ascacio-Martínez, María E. Gamino-Peña, Ricardo M. Cerda-Flores, Irene Meester, Hugo L. Gallardo-Blanco, Magdalena Gómez-Silva, Everardo Piñeyro-Garza, Hugo A. Barrera-Saldaña

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Abstract

Background: The genetic variation underlying atorvastatin (ATV) pharmacokinetics was evaluated in a Mexican population. Aims of this study were: 1) to reveal the frequency of 87 polymorphisms in 36 genes related to drug metabolism in healthy Mexican volunteers, 2) to evaluate the impact of these polymorphisms on ATV pharmacokinetics, 3) to classify the ATV metabolic phenotypes of healthy volunteers, and 4) to investigate a possible association between genotypes and metabolizer phenotypes. Methods: A pharmacokinetic study of ATV (single 80-mg dose) was conducted in 60 healthy male volunteers. ATV plasma concentrations were measured by high-performance liquid chromatography mass spectrometry. Pharmacokinetic parameters were calculated by the non-compartmental method. The polymorphisms were determined with the PHARMAchip® microarray and the TaqMan® probes genotyping assay. Results: Three metabolic phenotypes were found in our population: slow, normal, and rapid. Six gene polymorphisms were found to have a significant effect on ATV pharmacokinetics: MTHFR (rs1801133), DRD3 (rs6280), GSTM3 (rs1799735), TNFaα (rs1800629), MDR1 (rs1045642), and SLCO1B1 (rs4149056). The combination of MTHFR, DRD3 and MDR1 polymorphisms associated with a slow ATV metabolizer phenotype. Conclusion: Further studies using a genetic preselection method and a larger population are needed to confirm these polymorphisms as predictive biomarkers for ATV slow metabolizers. Trial registration: Australian New Zealand Clinical Trials Registry: ACTRN12614000851662 , date registered: August 8, 2014.

Original language	English
Article number	74
Pages (from-to)	74
Journal	BMC Cancer
Volume	16
Issue number	1
DOIs	https://doi.org/10.1186/s12885-016-2062-2
Publication status	Published - 8 Feb 2016

Bibliographical note

Funding Information:
Research was mainly supported by Ipharma S.A., Monterrey, Mexico. We thank the technical staff of Ipharma, S.A. and Vitagenesis, S.A. for facilities, advice and technical support. We also thank Lourdes Garza-Rodríguez and Herminia G. Martínez-Rodríguez for valuable suggestions.

Publisher Copyright:
© 2016 León-Cachón et al.

All Science Journal Classification (ASJC) codes

Oncology
Genetics
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1186/s12885-016-2062-2

Cite this

León-Cachón, R. B. R., Ascacio-Martínez, J. A., Gamino-Peña, M. E., Cerda-Flores, R. M., Meester, I., Gallardo-Blanco, H. L., Gómez-Silva, M., Piñeyro-Garza, E., & Barrera-Saldaña, H. A. (2016). A pharmacogenetic pilot study reveals MTHFR, DRD3, and MDR1 polymorphisms as biomarker candidates for slow atorvastatin metabolizers. BMC Cancer, 16(1), 74. Article 74. https://doi.org/10.1186/s12885-016-2062-2

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title = "A pharmacogenetic pilot study reveals MTHFR, DRD3, and MDR1 polymorphisms as biomarker candidates for slow atorvastatin metabolizers",

abstract = "Background: The genetic variation underlying atorvastatin (ATV) pharmacokinetics was evaluated in a Mexican population. Aims of this study were: 1) to reveal the frequency of 87 polymorphisms in 36 genes related to drug metabolism in healthy Mexican volunteers, 2) to evaluate the impact of these polymorphisms on ATV pharmacokinetics, 3) to classify the ATV metabolic phenotypes of healthy volunteers, and 4) to investigate a possible association between genotypes and metabolizer phenotypes. Methods: A pharmacokinetic study of ATV (single 80-mg dose) was conducted in 60 healthy male volunteers. ATV plasma concentrations were measured by high-performance liquid chromatography mass spectrometry. Pharmacokinetic parameters were calculated by the non-compartmental method. The polymorphisms were determined with the PHARMAchip{\textregistered} microarray and the TaqMan{\textregistered} probes genotyping assay. Results: Three metabolic phenotypes were found in our population: slow, normal, and rapid. Six gene polymorphisms were found to have a significant effect on ATV pharmacokinetics: MTHFR (rs1801133), DRD3 (rs6280), GSTM3 (rs1799735), TNFaα (rs1800629), MDR1 (rs1045642), and SLCO1B1 (rs4149056). The combination of MTHFR, DRD3 and MDR1 polymorphisms associated with a slow ATV metabolizer phenotype. Conclusion: Further studies using a genetic preselection method and a larger population are needed to confirm these polymorphisms as predictive biomarkers for ATV slow metabolizers. Trial registration: Australian New Zealand Clinical Trials Registry: ACTRN12614000851662 , date registered: August 8, 2014.",

author = "Le{\'o}n-Cach{\'o}n, {Rafael B.R.} and Ascacio-Mart{\'i}nez, {Jorge A.} and Gamino-Pe{\~n}a, {Mar{\'i}a E.} and Cerda-Flores, {Ricardo M.} and Irene Meester and Gallardo-Blanco, {Hugo L.} and Magdalena G{\'o}mez-Silva and Everardo Pi{\~n}eyro-Garza and Barrera-Salda{\~n}a, {Hugo A.}",

note = "Funding Information: Research was mainly supported by Ipharma S.A., Monterrey, Mexico. We thank the technical staff of Ipharma, S.A. and Vitagenesis, S.A. for facilities, advice and technical support. We also thank Lourdes Garza-Rodr{\'i}guez and Herminia G. Mart{\'i}nez-Rodr{\'i}guez for valuable suggestions. Publisher Copyright: {\textcopyright} 2016 Le{\'o}n-Cach{\'o}n et al.",

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León-Cachón, RBR, Ascacio-Martínez, JA, Gamino-Peña, ME, Cerda-Flores, RM, Meester, I, Gallardo-Blanco, HL, Gómez-Silva, M, Piñeyro-Garza, E & Barrera-Saldaña, HA 2016, 'A pharmacogenetic pilot study reveals MTHFR, DRD3, and MDR1 polymorphisms as biomarker candidates for slow atorvastatin metabolizers', BMC Cancer, vol. 16, no. 1, 74, pp. 74. https://doi.org/10.1186/s12885-016-2062-2

TY - JOUR

T1 - A pharmacogenetic pilot study reveals MTHFR, DRD3, and MDR1 polymorphisms as biomarker candidates for slow atorvastatin metabolizers

AU - León-Cachón, Rafael B.R.

AU - Ascacio-Martínez, Jorge A.

AU - Gamino-Peña, María E.

AU - Cerda-Flores, Ricardo M.

AU - Meester, Irene

AU - Gallardo-Blanco, Hugo L.

AU - Gómez-Silva, Magdalena

AU - Piñeyro-Garza, Everardo

AU - Barrera-Saldaña, Hugo A.

N1 - Funding Information: Research was mainly supported by Ipharma S.A., Monterrey, Mexico. We thank the technical staff of Ipharma, S.A. and Vitagenesis, S.A. for facilities, advice and technical support. We also thank Lourdes Garza-Rodríguez and Herminia G. Martínez-Rodríguez for valuable suggestions. Publisher Copyright: © 2016 León-Cachón et al.

PY - 2016/2/8

Y1 - 2016/2/8

N2 - Background: The genetic variation underlying atorvastatin (ATV) pharmacokinetics was evaluated in a Mexican population. Aims of this study were: 1) to reveal the frequency of 87 polymorphisms in 36 genes related to drug metabolism in healthy Mexican volunteers, 2) to evaluate the impact of these polymorphisms on ATV pharmacokinetics, 3) to classify the ATV metabolic phenotypes of healthy volunteers, and 4) to investigate a possible association between genotypes and metabolizer phenotypes. Methods: A pharmacokinetic study of ATV (single 80-mg dose) was conducted in 60 healthy male volunteers. ATV plasma concentrations were measured by high-performance liquid chromatography mass spectrometry. Pharmacokinetic parameters were calculated by the non-compartmental method. The polymorphisms were determined with the PHARMAchip® microarray and the TaqMan® probes genotyping assay. Results: Three metabolic phenotypes were found in our population: slow, normal, and rapid. Six gene polymorphisms were found to have a significant effect on ATV pharmacokinetics: MTHFR (rs1801133), DRD3 (rs6280), GSTM3 (rs1799735), TNFaα (rs1800629), MDR1 (rs1045642), and SLCO1B1 (rs4149056). The combination of MTHFR, DRD3 and MDR1 polymorphisms associated with a slow ATV metabolizer phenotype. Conclusion: Further studies using a genetic preselection method and a larger population are needed to confirm these polymorphisms as predictive biomarkers for ATV slow metabolizers. Trial registration: Australian New Zealand Clinical Trials Registry: ACTRN12614000851662 , date registered: August 8, 2014.

AB - Background: The genetic variation underlying atorvastatin (ATV) pharmacokinetics was evaluated in a Mexican population. Aims of this study were: 1) to reveal the frequency of 87 polymorphisms in 36 genes related to drug metabolism in healthy Mexican volunteers, 2) to evaluate the impact of these polymorphisms on ATV pharmacokinetics, 3) to classify the ATV metabolic phenotypes of healthy volunteers, and 4) to investigate a possible association between genotypes and metabolizer phenotypes. Methods: A pharmacokinetic study of ATV (single 80-mg dose) was conducted in 60 healthy male volunteers. ATV plasma concentrations were measured by high-performance liquid chromatography mass spectrometry. Pharmacokinetic parameters were calculated by the non-compartmental method. The polymorphisms were determined with the PHARMAchip® microarray and the TaqMan® probes genotyping assay. Results: Three metabolic phenotypes were found in our population: slow, normal, and rapid. Six gene polymorphisms were found to have a significant effect on ATV pharmacokinetics: MTHFR (rs1801133), DRD3 (rs6280), GSTM3 (rs1799735), TNFaα (rs1800629), MDR1 (rs1045642), and SLCO1B1 (rs4149056). The combination of MTHFR, DRD3 and MDR1 polymorphisms associated with a slow ATV metabolizer phenotype. Conclusion: Further studies using a genetic preselection method and a larger population are needed to confirm these polymorphisms as predictive biomarkers for ATV slow metabolizers. Trial registration: Australian New Zealand Clinical Trials Registry: ACTRN12614000851662 , date registered: August 8, 2014.

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A pharmacogenetic pilot study reveals MTHFR, DRD3, and MDR1 polymorphisms as biomarker candidates for slow atorvastatin metabolizers

Abstract

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A pharmacogenetic pilot study reveals MTHFR, DRD3, and MDR1 polymorphisms as biomarker candidates for slow atorvastatin metabolizers

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

UN SDGs

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