Pharmacogenetics and immunosuppressive drugs

Hronová, Karolína; Šíma, Martin; Světlík, Svatopluk; Matousková, O; Slanař, Ondřej

doi:10.1586/17512433.2014.966811

Cited by 11 publications

(8 citation statements)

References 86 publications

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“…tacrolimus, cyclosporine, everolimus). Most of these studies have been retrospective in design and the most relevant associations correspond to variants in CYP3A5 and ABCB1 [28,29], [30,31], however, most studies of everolimus pharmacokinetics have given negative results[32,33,34,35]. In this study, we found that CYP3A4*22 resulted in significantly higher plasma levels of everolimus, consistent with the decreased activity caused by the CYP3A4*22 allele [21], while no effect was detected for CYP3A5*3 with the same number of carrier patients This suggests a greater influence of CYP3A4*22 than CYP3A5*3 in everolimus pharmacokinetics, at least in MBC patients.…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms associated with everolimus pharmacokinetics, toxicity and survival in metastatic breast cancer

et al. 2017

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PurposeMetastatic breast cancer (MBC) progressing after endocrine therapy frequently activates PI3K/AKT/mTOR pathway. The BOLERO-2 trial showed that everolimus-exemestane achieves increased progression free survival (PFS) compared with exemestane. However, there is great inter-patient variability in toxicity and response to exemestane-everolimus treatment. The objective of this study was to perform an exploratory study analyzing the implication of single nucleotide polymorphisms (SNPs) on outcomes from this treatment through a pharmacogenetic analysis.Patients and methodsBlood was collected from 90 postmenopausal women with hormone receptor-positive, HER2-negative MBC treated with exemestane-everolimus following progression after prior treatment with a non-steroidal aromatase inhibitor. Everolimus pharmacokinetics was measured in 37 patients. Twelve SNPs in genes involved in everolimus pharmacokinetics and pharmacodynamics were genotyped and associations assessed with drug plasma levels, clinically relevant toxicities (non-infectious pneumonitis, mucositis, hyperglycemia and hematological toxicities), dose reductions or treatment suspensions due to toxicity, progression free survival (PFS) and overall survival.ResultsWe found that CYP3A4 rs35599367 variant (CYP3A4*22 allele) carriers had higher everolimus blood concentration compared to wild type patients (P = 0.019). ABCB1 rs1045642 was associated with risk of mucositis (P = 0.031), while PIK3R1 rs10515074 and RAPTOR rs9906827 were associated with hyperglycemia and non-infectious pneumonitis (P = 0.016 and 0.024, respectively). Furthermore, RAPTOR rs9906827 was associated with PFS (P = 0.006).ConclusionsCYP3A4*22 allele influenced plasma concentration of everolimus and several SNPs in PI3K/AKT/mTOR pathway genes were associated with treatment toxicities and prognosis. These results require replication, but suggest that germline variation could influence everolimus outcomes in MBC.

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Section: Discussionmentioning

confidence: 99%

Polymorphisms associated with everolimus pharmacokinetics, toxicity and survival in metastatic breast cancer

et al. 2017

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“…However, several factors influence the pharmacokinetics of tacrolimus, including hepatic dysfunction, post-transplantation time, hematocrit, serum albumin, age, race and drug interactions, especially gene polymorphism [ 5 ]. Single nucleotide polymorphisms (SNPs) in cytochrome P450 3A ( CYP3A ) play an important role in tacrolimus metabolism [ 6 ]. CYP3A enzymes in human liver microsomes play a major role in the oxidation of tacrolimus[ 7 ], and the tacrolimus metabolism within the small intestinal contributes significantly to its bioavailability[ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

Effects of the CYP3A4*1B Genetic Polymorphism on the Pharmacokinetics of Tacrolimus in Adult Renal Transplant Recipients: A Meta-Analysis

2015

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Background and ObjectiveThe association between the CYP3A4*1B single nucleotide polymorphism (SNP) and tacrolimus pharmacokinetics in different studies is controversial. Therefore, a meta-analysis was employed to evaluate the correlation between the CYP3A4*1B genetic polymorphism and tacrolimus pharmacokinetics at different post-transplantation times in adult renal transplant recipients.MethodsStudies evaluating the CYP3A4*1B genetic polymorphism and tacrolimus pharmacokinetics were retrieved through a systematical search of Embase, PubMed, the Cochrane Library, ClinicalTrials.gov and three Chinese literature databases (up to Sept. 2014). The pharmacokinetic parameters (weight-adjusted tacrolimus daily dose and tacrolimus trough concentration/weight-adjusted tacrolimus daily dose ratio) were extracted, and the meta-analysis was performed using Stata 12.1.ResultsSeven studies (involving 1182 adult renal transplant recipients) were included in this meta-analysis. For the weight-adjusted tacrolimus daily dose, in all included renal transplant recipients (European & Indian populations), CYP3A4*1/*1 recipients required a significantly lower weight-adjusted tacrolimus daily dose than did CYP3A4*1B carriers at 7 days (WMD -0.048; 95% CI -0.083 ~ -0.014), 6 months (WMD -0.058; 95% CI -0.081 ~ -0.036) and 12 months (WMD - 0.061; 95% CI -0.096 ~ -0.027) post-transplantation. In light of the heterogeneity, the analysis was repeated after removing the only study in an Indian population, and CYP3A4*1/*1 European recipients (mostly Caucasian) required a lower weight-adjusted tacrolimus daily dose within the first year post-transplantation. The tacrolimus trough concentration/weight-adjusted tacrolimus daily dose ratio (C0/Dose ratio) was significantly higher in CYP3A4*1/*1 recipients than in CYP3A4*1B carriers at 6 months (WMD 52.588; 95% CI 22.387 ~ 82.789) and 12 months (WMD 62.219; 95% CI 14.218 ~ 110.221) post-transplantation. When the only study in an Indian population was removed to examine European recipients (mostly Caucasian), the significant difference persisted at 1 month, 6 months and 12 months post-transplantation.ConclusionBased on our meta-analysis, the CYP3A4*1B genetic polymorphism affects tacrolimus dose requirements and tacrolimus trough concentration/weight-adjusted tacrolimus daily dose ratio within the first year post-transplantation in adult renal transplant recipients, especially in European recipients (mostly Caucasian).

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“…13–15,27,28 While there have been great advances in methylation-dependent bioinformatics and disease-associated biomarkers, 29–31 the study of intracellular MT spatial/temporal resolution, specificity, and/or function remains a challenge. 9,14,15,25–28,32–36 Toward this end, the pioneering demonstration of AdoMet analogs, bearing alternative alkyl donor substituents, as cosubstrates for DNA 37 or natural product (NP) 38 MTs has inspired new tools and strategies to study NP, 39–42 protein, 43–51 and nucleic acid 6,52–57 methylation where the recent development of enzyme-based strategies for the synthesis of differentially alkylated AdoMet analogs has simplified access to these unique cosubstrates. 42,49,50,57–59 However, the stability of AdoMet or its corresponding differentially alkylated analogs under physiological conditions limits their utility as reagents or therapeutics by virtue of two fundamental degradative processes: intramolecular cyclization to homoserine lactone and 5′-deoxy-5′-(alkylthio)adenosine (Figure 1, pathway a) and depurination (Figure 1, pathway b).…”

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confidence: 99%

Functional AdoMet Isosteres Resistant to Classical AdoMet Degradation Pathways

et al. 2016

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S-adenosyl-l-methionine (AdoMet) is an essential enzyme cosubstrate in fundamental biology with an expanding range of biocatalytic and therapeutic applications. We report the design, synthesis, and evaluation of stable, functional AdoMet isosteres that are resistant to the primary contributors to AdoMet degradation (depurination, intramolecular cyclization, and sulfonium epimerization). Corresponding biochemical and structural studies demonstrate the AdoMet surrogates to serve as competent enzyme cosubstrates and to bind a prototypical class I model methyltransferase (DnrK) in a manner nearly identical to AdoMet. Given this conservation in function and molecular recognition, the isosteres presented are anticipated to serve as useful surrogates in other AdoMet-dependent processes and may also be resistant to, and/or potentially even inhibit, other therapeutically relevant AdoMet-dependent metabolic transformations (such as the validated drug target AdoMet decarboxylase). This work also highlights the ability of the prototypical class I model methyltransferase DnrK to accept non-native surrogate acceptors as an enabling feature of a new high-throughput methyltransferase assay.

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Pharmacogenetics and immunosuppressive drugs

Cited by 11 publications

References 86 publications

Polymorphisms associated with everolimus pharmacokinetics, toxicity and survival in metastatic breast cancer

Polymorphisms associated with everolimus pharmacokinetics, toxicity and survival in metastatic breast cancer

Effects of the CYP3A4*1B Genetic Polymorphism on the Pharmacokinetics of Tacrolimus in Adult Renal Transplant Recipients: A Meta-Analysis

Functional AdoMet Isosteres Resistant to Classical AdoMet Degradation Pathways

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