<i>CYP3A5*3</i>
            and
            <i>CYP2C8*3</i>
            Variants Influence Exposure and Clinical Outcomes of Tacrolimus-Based Therapy

Genvigir, Fabiana Dalla Vecchia; Campos-Salazar, Antony Brayan; Felipe, Cláudia Rosso; Tedesco‐Silva, Hélio; Medina‐Pestana, José Osmar; Doi, Sonia Q.; Cerda, Álvaro; Hirata, Mário Hiroyuki; Herrero, Marí­a José; Aliño, Salvador F.; Hirata, Rosário Dominguez Crespo

doi:10.2217/pgs-2019-0120

Cited by 15 publications

(4 citation statements)

References 52 publications

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“…Moreover, novel variants in non-exonic regions might have a functional impact in drug responses, for example, our group recently analyzed the promoter region of CYP2C19 identifying novel SNVs that could potentially disrupt its binding activity to transcription factors and alter clopidogrel response ( Angulo-Aguado et al, 2021 ). In addition, important pharmacogenetic variants such as CYP3A5*3, related to immunosuppressive drug response, or CYP2C19*35 , related to clopidogrel response, are located in intronic regions not assessed by WES ( Genvigir et al, 2020 ; Angulo-Aguado et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Characterization of ADME Gene Variation in Colombian Population by Exome Sequencing

Silgado-Guzmán¹,

Angulo-Aguado

Morel

et al. 2022

Front. Pharmacol.

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In genes related to drug pharmacokinetics, molecular variations determine interindividual variability in the therapeutic efficacy and adverse drug reactions. The assessment of single-nucleotide variants (SNVs) is used with growing frequency in pharmacogenetic practice, and recently, high-throughput genomic analyses obtained through next-generation sequencing (NGS) have been recognized as powerful tools to identify common, rare and novel variants. These genetic profiles remain underexplored in Latin-American populations, including Colombia. In this study, we investigated the variability of 35 genes included in the ADME core panel (absorption, distribution, metabolism, and excretion) by whole-exome sequencing (WES) of 509 unrelated Colombian individuals with no previous reports of adverse drug reactions. Rare variants were filtered according to the minor allele frequencies (MAF) <1% and potential deleterious consequences. The functional impact of novel and rare missense variants was assessed using an optimized framework for pharmacogenetic variants. Bioinformatic analyses included the identification of clinically validated variants described in PharmGKB and ClinVar databases. Ancestry from WES data was inferred using the R package EthSEQ v2.1.4. Allelic frequencies were compared to other populations reported in the public gnomAD database. Our analysis revealed that rare missense pharmacogenetic variants were 2.1 times more frequent than common variants with 121 variants predicted as potentially deleterious. Rare loss of function (LoF) variants were identified in 65.7% of evaluated genes. Regarding variants with clinical pharmacogenetic effect, our study revealed 89 sequence variations in 28 genes represented by missense (62%), synonymous (22.5%), splice site (11.2%), and indels (3.4%). In this group, ABCB1, ABCC2, CY2B6, CYP2D6, DPYD, NAT2, SLC22A1, and UGTB2B7, are the most polymorphic genes. NAT2, CYP2B6 and DPYD metabolizer phenotypes demonstrated the highest variability. Ancestry analysis indicated admixture in 73% of the population. Allelic frequencies exhibit significant differences with other Latin-American populations, highlighting the importance of pharmacogenomic studies in populations of different ethnicities. Altogether, our data revealed that rare variants are an important source of variability in pharmacogenes involved in the pharmacokinetics of drugs and likely account for the unexplained interindividual variability in drug response. These findings provide evidence of the utility of WES for pharmacogenomic testing and into clinical practice.

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Section: Discussionmentioning

confidence: 99%

Characterization of ADME Gene Variation in Colombian Population by Exome Sequencing

Silgado-Guzmán¹,

Angulo-Aguado

Morel

et al. 2022

Front. Pharmacol.

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“…Compared to CYP3A5 * 3/ * 3 carriers, CYP3A5 * 1 carriers show increased metabolism of tacrolimus. 24 Tacrolimus is transported out of the cells via P-glycoprotein, which is encoded by the ABCB1 gene. 25 The highly variable intestinal expression of ABCB1 is an important determinant of the tacrolimus absorption.…”

Section: Discussionmentioning

confidence: 99%

Flat Pattern Peaks of Tacrolimus Absorption and Associated Pharmacogenomic Variants in Kidney Transplantation Recipients

et al. 2022

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Background Tacrolimus is the most commonly used immunosuppressive drug in solid organ transplantation. After administering a conventional twice-daily dose of tacrolimus, peak levels were achieved within the first 1.5 to 2 hours. A group of patients showed different early absorption phase of tacrolimus after kidney transplantation. Methods Trough(C 0 ) and 1.5-hour blood levels (C 1.5 ) of tacrolimus were measured in 95 kidney transplantation recipients. Patients with a C 1.5 /C 0 < 1.5 and > 1.5 were defined as those having flat pattern peaks and as controls, respectively. Transplantation outcomes were compared between the groups. Whole exome sequencing was performed to investigate the genetic susceptibility to flat pattern peaks. Results Twenty-eight patients showed flat pattern peaks. The mean C 1.5 /C 0 values were 1.13 ± 0.22 and 3.78 ± 1.25 in the flat pattern peak and control groups, respectively. In multivariate analysis, flat pattern peak was an independent risk factor for biopsy-proven acute rejection (BPAR) and/or borderline change ( P = 0.014). Patients having flat pattern peaks showed significantly lower post-transplant 36-month estimated glomerular filtration rate ( P = 0.001). Two single nucleotide variants in ABCB1 genes, rs1922242 and rs2235035, were associated with flat pattern peaks ( P = 0.019 and P = 0.027, respectively). Conclusion Both of C 1.5 and C 0 should be measured to distinguish the patients showing unique initial absorption. A C 1.5 /C 0 ratio lower than 1.5 was associated with an increased risk of BPAR and/or borderline change. Single nucleotide variants s in ABCB1 gene might influence the flat pattern peaks of tacrolimus absorption.

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“…CYP3A5 includes 25 allelic variants, of which CYP3A5*3 (g.6986A>G, rs776746, MAF 88.2%) is the most studied one, followed by alleles *6 and *7 [76], whereas *3/*3 phenotype implies the absence of expression of this enzyme. Despite the confirmed role of CYP3A5 in the clearance of tacrolimus [38], it has not been consistently associated with the risk of acute rejection after organ transplantation in patients treated with this immunosuppressant. However, there is a dosing equation for the use of tacrolimus in adult kidney transplant recipients, which, together with days post-transplant and other individual factors, includes the CYP3A5 genotype [39].…”

Section: Cyp3a5mentioning

confidence: 99%

Role of Genetic Variations in the Hepatic Handling of Drugs

Marin

Serrano

Monte

et al. 2020

IJMS

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The liver plays a pivotal role in drug handling due to its contribution to the processes of detoxification (phases 0 to 3). In addition, the liver is also an essential organ for the mechanism of action of many families of drugs, such as cholesterol-lowering, antidiabetic, antiviral, anticoagulant, and anticancer agents. Accordingly, the presence of genetic variants affecting a high number of genes expressed in hepatocytes has a critical clinical impact. The present review is not an exhaustive list but a general overview of the most relevant variants of genes involved in detoxification phases. The available information highlights the importance of defining the genomic profile responsible for the hepatic handling of drugs in many ways, such as (i) impaired uptake, (ii) enhanced export, (iii) altered metabolism due to decreased activation of prodrugs or enhanced inactivation of active compounds, and (iv) altered molecular targets located in the liver due to genetic changes or activation/downregulation of alternative/compensatory pathways. In conclusion, the advance in this field of modern pharmacology, which allows one to predict the outcome of the treatments and to develop more effective and selective agents able to overcome the lack of effect associated with the existence of some genetic variants, is required to step forward toward a more personalized medicine.

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CYP3A53* and CYP2C83* Variants Influence Exposure and Clinical Outcomes of Tacrolimus-Based Therapy

Cited by 15 publications

References 52 publications

Characterization of ADME Gene Variation in Colombian Population by Exome Sequencing

Characterization of ADME Gene Variation in Colombian Population by Exome Sequencing

Flat Pattern Peaks of Tacrolimus Absorption and Associated Pharmacogenomic Variants in Kidney Transplantation Recipients

Role of Genetic Variations in the Hepatic Handling of Drugs

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CYP3A5*3 and CYP2C8*3 Variants Influence Exposure and Clinical Outcomes of Tacrolimus-Based Therapy

Cited by 15 publications

References 52 publications

Characterization of ADME Gene Variation in Colombian Population by Exome Sequencing

Characterization of ADME Gene Variation in Colombian Population by Exome Sequencing

Flat Pattern Peaks of Tacrolimus Absorption and Associated Pharmacogenomic Variants in Kidney Transplantation Recipients

Role of Genetic Variations in the Hepatic Handling of Drugs

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CYP3A53* and CYP2C83* Variants Influence Exposure and Clinical Outcomes of Tacrolimus-Based Therapy