Prediction of Atorvastatin Plasmatic Concentrations in Healthy Volunteers Using Integrated Pharmacogenetics Sequencing

Cruz-Correa, Omar Fernando; León-Cachón, Rafael B. R.; Barrera-Saldaña, Hugo A.; Soberón, Xavier

doi:10.2217/pgs-2016-0072

Cited by 13 publications

(14 citation statements)

References 36 publications

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“…However, there is little information about the role of CYP2D6 in ATV metabolism or pharmacokinetics. In a previous study, CYP2D6-rs1135840 seemed to have a significant effect on AUC values 13 , but this finding was not confirmed in this study. Here, we identified that CYP2D6-rs1135840 has a significant effect on Ke and T 1/2 parameters, but this was not confirmed with the regression analyses, so its effect on the metabolism and excretion phases is not clear.…”

Section: Discussioncontrasting

confidence: 99%

“…In addition, synergistic or antagonistic interactions with other gene variants may create variability. So far, evidence on synergistic or antagonistic effect of ABCB1 on ATV plasma concentrations is scarce 13 .The significantly lower values in C/C carriers and the dominant effect of allele T suggest that the rs1045642 polymorphism significantly affects the absorption, bioavailability and blood concentrations of ATV. This hypothesis is supported by the intestinal expression of ABCB1, where this transporter actively participates in drug absorption 24 .…”

Section: Discussionmentioning

confidence: 99%

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The atorvastatin metabolic phenotype shift is influenced by interaction of drug-transporter polymorphisms in Mexican population: results of a randomized trial

León-Cachón

Bamford

Meester

et al. 2020

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Atorvastatin (ATV) is a blood cholesterol-lowering drug used to prevent cardiovascular events, the leading cause of death worldwide. As pharmacokinetics, metabolism and response vary among individuals, we wanted to determine the most reliable metabolic ATV phenotypes and identify novel and preponderant genetic markers that affect ATV plasma levels. A controlled, randomized, crossover, single-blind, three-treatment, three-period, and six-sequence clinical study of ATV (single 80-mg oral dose) was conducted among 60 healthy Mexican men. ATV plasma levels were measured using highperformance liquid chromatography mass spectrometry. Genotyping was performed by real-time PCR with TaqMan probes. Four ATV metabolizer phenotypes were found: slow, intermediate, normal and fast. Six gene polymorphisms, SLCO1B1-rs4149056, ABCB1-rs1045642, CYP2D6-rs1135840, CYP2B6-rs3745274, NAT2-rs1208, and COMT-rs4680, had a significant effect on ATV pharmacokinetics (P < 0.05). The polymorphisms in SLCO1B1 and ABCB1 seemed to have a greater effect and were especially important for the shift from an intermediate to a normal metabolizer. This is the first study that demonstrates how the interaction of genetic variants affect metabolic phenotyping and improves understanding of how SLCO1B1 and ABCB1 variants that affect statin metabolism may partially explain the variability in drug response. Notwithstanding, the influence of other genetic and non-genetic factors is not ruled out. Cardiovascular diseases (CVD) are the leading cause of death worldwide 1 and in Mexico 2. Diet, a lack of physical activity, and ageing are risk factors for CVD, but smoking, a high blood pressure and a high blood cholesterol level are at the top 3. Statins are the first-choice drugs to treat hypercholesterolemia, and atorvastatin (ATV) is one of the most used statins 4,5. However, interindividual variability in both ATV metabolism 6-8 and therapeutic response 9-11 have been reported. Three ATV metabolic phenotypes have been identified 6,8,12 and non-validated massive genotyping methods identified genetic variants that seemed to impact ATV pharmacokinetics 6,13. The classification of metabolic phenotypes is challenging because of large datasets, variables at different scales, and limited knowledge on phenotyping data management 14. Gene expression studies on large data sets of tissue

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The atorvastatin metabolic phenotype shift is influenced by interaction of drug-transporter polymorphisms in Mexican population: results of a randomized trial

León-Cachón

Bamford

Meester

et al. 2020

Sci Rep

Self Cite

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“…The inclusion of these biomarkers in future studies may improve the prediction of the pharmacokinetic variability of ATV or decrease the number of variants required for prediction (7,11). While the current study demonstrated the contribution of genetic polymorphisms to ATV pharmacokinetics, there were a number of limitations.…”

Section: Discussionmentioning

confidence: 82%

“…This reflects the underlying variability in the absorption, distribution, metabolism and excretion (ADME) processes of ATV, which may affect the pharmacological response (8). Although in general, genetic factors influence ~30% of variation in drug disposition and response (9,10), recent results have indicated that genetic variability may contribute to >90% of the variance in ATV plasma concentrations (11). These differences in the ADME characteristics of ATV have been attributed to polymorphisms in genes associated with drug pharmacokinetics, particularly those encoding enzymes and transporters (7,10,11).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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Abstract. Discrepancies in the response to drugs are partially due to polymorphisms in genes involved in drug metabolism and transport. The frequency, pattern and impact of these polymorphisms vary among populations. In the present study, the pharmacokinetics and pharmacogenetics of atorvastatin (ATV) in a Mexican population were investigated. The study cohort exhibited differing ATV metabolizing phenotypes, and in subsequent allelic discrimination assays, single nucleotide polymorphisms in the angiotensinogen, angiotensin II type 1 receptor (AGTR1) and bradykinin B2 receptor (BDKRB2) genes were genotyped and their effects on the pharmacokinetic parameters of ATV were assessed. Additionally, association studies were performed to test for a correlation between metabolizing phenotypes and genetic variants. It was observed that carriers of the genotypes A/C and C/T in AGTR1 and BDKRB2 had higher area under the plasma concentration-time curve values from time 0 to the time of the last measurement and from time 0 extrapolated to infinity, and lower values of clearance of the fraction dose absorbed compared with homozygous carriers (P<0.05). Only the C/C genotype of BDKRB2 was associated with the fast metabolizer phenotype. These data suggest that AGTR1 and BDKRB2 are involved in ATV pharmacokinetics; a novel finding that requires confirmation in further studies.

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“…We identified a new variant on CYP2D8P POS.42547668, 26 Kbp upstream CYP2D6 , and although there is no xenobiotic metabolism reported for this pseudogene, we can speculate that this variant is in LD with another one affecting gene expression or drug metabolism. The inclusion of many variants to dissect a pharmacogenetic phenotype is becoming more common as it increases our knowledge in paths and network interactions not previously considered (Cruz-Correa et al, 2017 ; Oliveira-Paula et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Pharmacogenetic Variation in Over 100 Genes in Patients Receiving Acenocumarol

et al. 2017

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Coumarins are widely prescribed worldwide, and in Mexico acenocumarol is the preferred form. It is well known that despite its efficacy, coumarins show a high variability for dose requirements. We investigated the pharmacogenetic variation of 110 genes in patients receiving acenocumarol using a targeted NGS approach. We report relevant population differentiation for variants on CYP2C8, CYP2C19, CYP4F11, CYP4F2, PROS, and GGCX, VKORC1, CYP2C18, NQO1. A higher proportion of novel-to-known variants for 10 genes was identified on 41 core pharmacogenomics genes related to the PK (29), PD (3), of coumarins, and coagulation proteins (9) including, CYP1A1, CYP3A4, CYP3A5, and F8, and a low proportion of novel-to-known variants on CYP2E1, VKORC1, and SULT1A1/2. Using a Bayesian approach, we identified variants influencing acenocumarol dosing on, VKORC1 (2), SULT1A1 (1), and CYP2D8P (1) explaining 40–55% of dose variability. A collection of pharmacogenetic variation on 110 genes related to the PK/PD of coumarins is also presented. Our results offer an initial insight into the use of a targeted NGS approach in the pharmacogenomics of coumarins in Mexican Mestizos.

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Prediction of Atorvastatin Plasmatic Concentrations in Healthy Volunteers Using Integrated Pharmacogenetics Sequencing

Abstract: An integrated analysis of several genes known to intervene in the different steps of metabolism is required to predict atorvastatin's AUC.

Cited by 13 publications

References 36 publications

The atorvastatin metabolic phenotype shift is influenced by interaction of drug-transporter polymorphisms in Mexican population: results of a randomized trial

The atorvastatin metabolic phenotype shift is influenced by interaction of drug-transporter polymorphisms in Mexican population: results of a randomized trial

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

Pharmacogenetic Variation in Over 100 Genes in Patients Receiving Acenocumarol

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