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

Abstract

BackgroundThe 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.MethodsA 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.ResultsThree 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.ConclusionFurther studies using a genetic preselection method and a larger population are needed to confirm these polymorphisms as predictive biomarkers for ATV slow metabolizers.Trial registrationAustralian New Zealand Clinical Trials Registry: ACTRN12614000851662, date registered: August 8, 2014.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2062-2) contains supplementary material, which is available to authorized users.

Effect of AGTR1 and BDKRB2 gene polymorphisms on atorvastatin metabolism in a Mexican population

“…The study was performed according to the guidelines of the Declaration of Helsinki (22) Study population. As described in our preliminary pilot study (7), a total of 60 healthy male volunteers of Mexican origin were included in the study from January 2011 to February 2011, with a mean age of 24.01±4.35 years. The inclusion criteria were as follows: Non-smoker; 18-45 years old; weight, ≥50 kg; body mass index, 20-26 kg/m 2 ; availability to complete the study and normal health status (free from disease).…”

“…ATV administration and blood sampling were performed as described in the pilot study (7). Briefly, peripheral blood (4 ml) was collected in K 2 EDTA-coated BD Vacutainers ® (BD Diagnostics, Franklin Lakes, NJ, USA) at different time points: Prior to drug administration (time 0) and at 17 time points (0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 36 and 48 h) after drug administration.…”

“…ATV plasma concentrations were measured by high-performance liquid chromatography tandem mass spectrometry with an Agilent 1100 system (Agilent Technologies, Inc., Santa Clara, CA, USA) using a method validated by Ipharma S.A. (7,27,28). The C max and Tmax parameters were obtained from the concentration-time data of the plasma.…”

“…The C max and Tmax parameters were obtained from the concentration-time data of the plasma. Pharmacokinetic parameters including AUC 0-t , AUC 0-∞ , Cl/F, Ke, and T 1/2 , were calculated with a non-compartmental method (29) using WinNonlin ® software v5.3 (Pharsight Corp., Mountain View, CA, USA) as described in the pilot study (7).…”

“…As a consequence, low-density lipoprotein cholesterol uptake by liver cells increases and blood cholesterol levels diminish (6). However, in clinical trials of ATV, pharmacokinetic parameters including maximum plasma concentration (C max ), time to reach C max (T max ), area under the plasma concentration-time curve (AUC) from time 0 to the time of last measurement (AUC 0-t ), AUC from time 0 extrapolated to infinity (AUC 0-∞ ), apparent clearance of the fraction dose absorbed (Cl/F), elimination rate constant in the terminal drug phase (Ke) and the half-life in the terminal drug phase (T 1/2 ) are variable (7). This reflects the underlying variability in the absorption, distribution, metabolism and excretion (ADME) processes of ATV, which may affect the pharmacological response (8).…”