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

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

© 2016 León-Cachón et al. 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 languageEnglish
Article number74
JournalBMC Cancer
Volume16
Issue number1
DOIs
Publication statusPublished - 8 Feb 2016

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Biomarkers
Pharmacokinetics
Phenotype
Healthy Volunteers
Population
Pharmacogenomic Testing
Atorvastatin Calcium
New Zealand
Genes
Registries
Mass Spectrometry
Genotype
High Pressure Liquid Chromatography
Clinical Trials
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Oncology
  • Genetics
  • Cancer Research

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., ... 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]. https://doi.org/10.1186/s12885-016-2062-2
León-Cachón, Rafael B.R. ; Ascacio-Martínez, Jorge A. ; Gamino-Peña, María E. ; Cerda-Flores, Ricardo M. ; Meester, Irene ; Gallardo-Blanco, Hugo L. ; Gómez-Silva, Magdalena ; Piñeyro-Garza, Everardo ; Barrera-Saldaña, Hugo A. / A pharmacogenetic pilot study reveals MTHFR, DRD3, and MDR1 polymorphisms as biomarker candidates for slow atorvastatin metabolizers. In: BMC Cancer. 2016 ; Vol. 16, No. 1.
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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. https://doi.org/10.1186/s12885-016-2062-2

A pharmacogenetic pilot study reveals MTHFR, DRD3, and MDR1 polymorphisms as biomarker candidates for slow atorvastatin metabolizers. / León-Cachón, Rafael B.R.; Ascacio-Martínez, Jorge A.; Gamino-Peña, María E.; Cerda-Flores, Ricardo M.; Meester, Irene; Gallardo-Blanco, Hugo L.; Gómez-Silva, Magdalena; Piñeyro-Garza, Everardo; Barrera-Saldaña, Hugo A.

In: BMC Cancer, Vol. 16, No. 1, 74, 08.02.2016.

Research output: Contribution to journalArticle

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.

PY - 2016/2/8

Y1 - 2016/2/8

N2 - © 2016 León-Cachón et al. 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 - © 2016 León-Cachón et al. 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.

U2 - 10.1186/s12885-016-2062-2

DO - 10.1186/s12885-016-2062-2

M3 - Article

VL - 16

JO - BMC Cancer

JF - BMC Cancer

SN - 1471-2407

IS - 1

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ER -