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® 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), TNFα (rs1800629), MDR1 (rs1045642), and SLCO1B1 (rs4149056). The combination of MTHFR, DRD3 and MDR1 polymorphisms associated with a slow ATV metabolizer phenotype.
  
  
  CONCLUSIONS
  Further studies using a genetic preselection method and a larger population are needed to confirm these polymorphisms as predictive biomarkers for ATV slow metabolizers.
  
  
  BACKGROUND
  Australian New Zealand Clinical Trials Registry: ACTRN12614000851662, date registered: August 8, 2014.
authors: Centro de Diagnóstico Molecular y Medicina Personalizada, Departamento de Ciencias Básicas, División Ciencias de la Salud, Universidad de Monterrey, San Pedro Garza García, NL, México.|Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey, NL, México.
authors: Rafael B R
authors: RBR
authors: León-Cachón
authors: Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey, NL, México.
authors: Jorge A
authors: JA
authors: Ascacio-Martínez
authors: Ipharma S.A., Monterrey, NL, México.
authors: María E
authors: ME
authors: Gamino-Peña
authors: Facultad de Enfermería, Universidad Autónoma de Nuevo León, Monterrey, NL, México.
authors: Ricardo M
authors: RM
authors: Cerda-Flores
authors: Centro de Diagnóstico Molecular y Medicina Personalizada, Departamento de Ciencias Básicas, División Ciencias de la Salud, Universidad de Monterrey, San Pedro Garza García, NL, México.
authors: Irene
authors: I
authors: Meester
authors: Departamento de Genética, Universidad Autónoma de Nuevo León, Monterrey, NL, México.
authors: Hugo L
authors: HL
authors: Gallardo-Blanco
authors: Ipharma S.A., Monterrey, NL, México.
authors: Magdalena
authors: M
authors: Gómez-Silva
authors: Ipharma S.A., Monterrey, NL, México.
authors: Everardo
authors: E
authors: Piñeyro-Garza
authors: Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey, NL, México. habarrera@gmail.com.|Vitagénesis S.A., Monterrey, NL, México. habarrera@gmail.com.
authors: Hugo A
authors: HA
authors: Barrera-Saldaña
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000069059:Atorvastatin / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D054316:Biomarkers, Pharmacological; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics*; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D050637:Receptors, Dopamine D3 / Q000235:genetics*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D054316:Biomarkers, Pharmacological; C493593:DRD3 protein, human; D050637:Receptors, Dopamine D3; D000069059:Atorvastatin; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2)