scholarly journals Dexketoprofen Pharmacokinetics is not Significantly Altered by Genetic Polymorphism

2021 ◽  
Vol 12 ◽  
Author(s):  
Gina Mejía-Abril ◽  
Pablo Zubiaur ◽  
Marcos Navares-Gómez ◽  
Gonzalo Villapalos-García ◽  
Manuel Román ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Genetic Polymorphism ◽  
Univariate Analysis ◽  
Current Evidence ◽  
Nucleotide Polymorphisms ◽  
Pharmacokinetic Variability ◽  
Metabolizing Enzymes ◽  
Genes Encoding ◽  
Metabolizing Enzyme ◽  
Individualization Of Therapy

Dexketoprofen is the (S)-(+)-enantiomer of racemic ketoprofen, a nonsteroidal anti-inflammatory drug used for the management of different types of pain. To the best of our knowledge, no article was published to date on dexketoprofen pharmacogenetics. Thence, in this work, we aimed to explore the influence of sex, race and several single nucleotide polymorphisms (SNPs) in genes encoding metabolizing enzymes (e.g. CYP or UGT) or transporters (e.g., ABC or SLC) in the pharmacokinetics and safety of dexketoprofen to explore whether dosing adjustments based on genetic polymorphism would be beneficial for its prescription. For this regard, 85 healthy volunteers enrolled in three bioequivalence clinical trials were genotyped for 46 SNPs in 14 genes. Women showed lower AUC adjusted by dose/weight (AUC/DW) and higher Vd/F and Cl/F than men (p < 0.05 in univariate and multivariate analysis). CYP1A2*1B allele, CYP2B6 IM/PM and CYP2D6 IM/PM phenotypes were related to drug accumulation (AUC/DW or Cmax/DW) compared to the CYP1A2*1 allele, CYP2B6 NM/RM and CYP2D6 NM/UM phenotypes (p < 0.05 in the univariate analysis). ABCB1 C1236TT, C3435TT and G2677A/TA/T alleles were related to lower Cmax/DW compared to C, C, and G alleles (p < 0.05 in univariate and multivariate analysis). ABCB1 C1236TT allele was also related to lower AUC/DW (p < 0.05 in multivariate analysis). The remaining studied transporter genes (ABCC2, SLC22A1, and SLCO1B1) and metabolizing enzyme genes (CYP3A5, CYP2C19, CYP2C9, CYP2C8, CYP3A4, CYP2A6, and UGT1A1) were unrelated to dexketoprofen pharmacokinetic variability. We conclude that dexketoprofen pharmacokinetics can be influenced by several polymorphisms, although there is not a clear pharmacogenetic predictor that would justify individualization of therapy based on its genotyping. Further studies should be conducted to confirm the role of SNPs in CYP2B6, CYP2D6, CYP1A2 and ABCB1 on the pharmacokinetic variability of dexketoprofen. Current evidence on dexketoprofen pharmacogenetics does not justify its inclusion in pharmacogenetic guidelines.

Influence of CYP3A4 and CYP3A5 polymorphisms on tacrolimus and sirolimus exposure in stable kidney transplant recipients

2017 ◽  
Vol 32 (2) ◽  
Author(s):  
Erika Y. Tamashiro ◽  
Claudia R. Felipe ◽  
Fabiana D.V. Genvigir ◽  
Alice C. Rodrigues ◽  
Antony B. Campos ◽  
...  
Keyword(s):  
Kidney Transplant ◽  
Drug Metabolizing Enzymes ◽  
Nucleotide Polymorphisms ◽  
Transplant Recipients ◽  
Pharmacokinetic Variability ◽  
Kidney Transplant Recipients ◽  
Metabolizing Enzymes ◽  
Single Nucleotide ◽  
Multiple Factors ◽  
Genes Encoding

AbstractBackground:Polymorphisms in genes encoding for drug-metabolizing enzymes and drug transporters are among multiple factors that modulate the pharmacokinetic variability of tacrolimus (TAC) and sirolimus (SRL). This study aimed to evaluate the influence of single nucleotide polymorphisms (SNPs) on TAC and SRL dose-adjusted concentrations (C0/D) in stable kidney transplant recipients.Methods:This is an exploratory and prospective study, which includes 46 stable kidney transplant recipients. These patients were monitored from the 3rd to the 24th month after transplantation. The SRL group consisted of 25 patients receiving TAC, prednisone (PRED), and mycophenolate sodium (MPS), which were converted from TAC to SRL at 3rd month after transplantation. The TAC group consisted of 21 patients who underwent treatment with TAC, PRED, and MPS. Both groups were genotyped forResults:In the TAC group,Conclusions:rs2242480 and

scholarly journals SNPs in genes encoding for IL-10, TNF-α, and NFκB p105/p50 are associated with clinical prognostic factors for patients with Hodgkin lymphoma

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0248259
Author(s):  
Rafael Dezen Gaiolla ◽  
Marcelo Padovani de Toledo Moraes ◽  
Deilson Elgui de Oliveira
Keyword(s):  
Hodgkin Lymphoma ◽  
Univariate Analysis ◽  
Stage Iv ◽  
Inflammatory Cells ◽  
Cytokine Gene Expression ◽  
Nucleotide Polymorphisms ◽  
Promoter Regions ◽  
Tnf Α ◽  
Mediastinal Disease ◽  
Genes Encoding

Classical Hodgkin lymphoma (cHL) is a B-cell-derived malignant neoplasia that has a unique histological distribution, in which the scarce malignant Hodgkin and Reed-Sternberg cells are surrounded by nonmalignant inflammatory cells. The interactions between the malignant and inflammatory cells are mediated by aberrantly produced cytokines, which play an important role in tumor immunopathogenesis. Single nucleotide polymorphisms (SNPs) in genes encoding cytokines and their regulatory proteins may influence the peripheral levels of these molecules and affect disease’s pathobiology. In this study, we evaluate SNPs in the promoter regions of the genes encoding for two key cytokines in Hodgkin lymphoma: IL-10 (SNP/pIL10–592, rs1800872; and SNP/pIL10–1082, rs1800896) and TNF-α (SNP/pTNF -238, rs361525; and SNP/pTNF -862, rs1800630), as well as an SNP in the intronic region of the NFκB1 gene (SNP/iNFKB1, rs1585215), an important regulator of cytokine gene expression. We then look to their possible association with clinical and laboratory features in cHL patients. Seventy-three patients with cHL are genotyped by qPCR-high resolution melting. The SNPs’ genotypes are analyzed individually for each SNP, and when more than two allelic combinations are identified, the genotypes are also divided into two groups according to proposed biological relevance. By univariate analysis, patients harboring SNP/pTNF -238 AG genotype more frequently have EBV-associated cHL compared to homozygous GG, whereas the presence of mediastinal disease (bulky and nonbulky) is more common in the pIL10–592 AC/CC group compared to the AA homozygous group. Patients with SNP/iNFKB1 AA genotype more frequently have stage IV and extranodal disease at diagnosis. These results indicate that some SNPs’ genotypes for IL-10 and TNF-α genes are associated with prognostic parameters in cHL. For the first time, the SNP/iNFKB1 is described in association with clinical features of the disease.

Pharmacogenetic pathway analysis for determination of sunitinib-induced toxicity

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5006-5006
Author(s):  
N. van Erp ◽  
R. H. Mathijssen ◽  
A. A. van der Veldt ◽  
J. B. Haanen ◽  
A. K. Reyners ◽  
...  
Keyword(s):  
Drug Targets ◽  
Single Agent ◽  
Mucosal Inflammation ◽  
Nucleotide Polymorphisms ◽  
Genetic Determinants ◽  
Metabolizing Enzymes ◽  
Genes Encoding ◽  
Hand Foot Syndrome ◽  
T Haplotype

5006 Background: To identify genetic markers in the pharmacokinetic and pharmacodynamic pathways of sunitinib that predispose for development of toxicities; thrombocytopenia, leukopenia, mucosal inflammation, hand-foot syndrome and ‘any toxicity according to Common Terminology Criteria > grade 2.’ Methods: A multicenter pharmacogenetic association study was performed in 219 patients treated with single agent sunitinib. A total of 31 single nucleotide polymorphisms in 12 candidate genes, together with several non-genetic variants, were analyzed for a possible association with toxicity. In addition, genetic haplotypes were developed and related to toxicity. Results: The risk for leukopenia was increased when the G-allele in CYP1A1 2455A/G (OR = 6.24; p = 0.029) or the T-allele in FLT3 738T/C (OR = 2.8; p = 0.008) were present or CAG in the NR1I3 (5719C/T, 7738A/C, 7837T/G) haplotype (OR = 1.74; p = 0.041) was absent. ‘Any toxicity > grade 2’ prevalence was increased when the T-allele of VEGFR-2 1191C/T (OR = 2.39; p = 0.046) or a copy of TT in the ABCG2 (-15622C/T, 1143C/T) haplotype (OR = 2.63; p = 0.016) were present. The risk for mucosal inflammation was increased in the presence of the G-allele in CYP1A1 2455A/G (OR = 4.03; p = 0.021) and the prevalence of hand-foot syndrome was increased when a copy of TTT in the ABCB1 (3435C/T, 1236C/T, 2677G/T) haplotype (OR = 2.56; p = 0.035) was present. Conclusions: This exploratory study suggests that polymorphisms in specific genes encoding for metabolizing enzymes, efflux transporters and drug targets are associated with sunitinib related toxicities. A better understanding of genetic and non-genetic determinants of sunitinib toxicity should help to optimize drug treatment in individual patients. [Table: see text]

ABCB1, CYP3A5*3, and CYP3A4*1B SNPs and risk of toxicity with sunitinib treatment for mRCC.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 485-485
Author(s):  
Maria Bassanelli ◽  
Alessandra Felici ◽  
Michele Milella ◽  
Diana Giannarelli ◽  
Silvana Giacinti ◽  
...  
Keyword(s):  
Nucleotide Polymorphisms ◽  
Test Results ◽  
Chi Square ◽  
Metabolizing Enzymes ◽  
Single Nucleotide ◽  
Genes Encoding ◽  
Hand Foot Syndrome ◽  
Chi Square Test ◽  
Grade 3 ◽  
The Individual

485 Background: Currently there are no biomarkers to predict either toxicity or activity of targeted therapy in mRCC. The aim of this study was to correlate single nucleotide polymorphisms (SNPs) of genes encoding for efflux transporters and metabolizing enzymes with sunitinib toxicity in metastatic renal cell carcinoma (mRCC) patients (pts). Methods: We conducted an observational, retrospective analysis of 60 Caucasian pts who received sunitinib for mRCC from 2 Italian institutions. Correlation between adverse events (AE, according to CTCAE v.4.0) and 4 polymorphisms in 3 genes (ABCB1 [1236C>T, 3435C>T], CYP3A5*3 6986A>G, CYP3A4*1B-392A>G) was analyzed. SNPs were detected in blood samples using pyrosequencing technique. Association between SNPs and toxicities was evaluated using the Chi Square test. Results: 60pts (median age: 61 years; male: 63.3%) with mRCC (clear cell: 85%, other histologies: 15%) were treated with sunitinib (83.3% as first-line). The most common AE (any-grade) reported were: hypertension (85%), asthenia (83.3%), hypothyroidism (65%), anemia (61.6%), nausea/vomiting (60%), stomatitis (58.3%), diarrhoea (48.3%), neutropenia (48.3%), thrombocytopenia (46.7%), leukopenia (46.7%), hypertriglyceridemia (45%), hyperglycaemia (38.4%), hypercholesterolemia (35%), and hand-foot syndrome (35%). Treatment was discontinued and sunitinib dose was reduced due to AE in 28.3% and 61.7% of pts, respectively. The G/A-variant in CYP3A5*3 was associated with thrombocytopenia (any grade, p=0.03); homozygous C/C alleles in ABCB1 1236C>T significantly correlated with leukopenia (any grade, p=0.01), while the C/C genotype in ABCB1 3435C>T was associated with hypertension (grade≥3, p=0.05); hypertriglyceridemia showed a trend towards increased prevalence in the presence of the C allele (grade≥3, p=0.08). Conclusions: Polymorphisms in ABCB1 and CYP3A5*3 are predictive of toxicity, as hypertension, leukopenia, and thrombocytopenia in pts with mRCC treated with sunitinib. This analysis could support the selection of the more appropriate drug to the individual patient.

scholarly journals Single Nucleotide Polymorphisms Associated with Methotrexate-induced Nausea in Juvenile Idiopathic Arthritis

2021 ◽  
Author(s):  
Nini Kyvsgaard ◽  
Torben Stamm Mikkelsen ◽  
Thomas D. Als ◽  
Anne Estmann Christensen ◽  
Thomas J. Corydon ◽  
...  
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Single Nucleotide Polymorphisms ◽  
Snp Analysis ◽  
Genotype Distribution ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Minor Alleles ◽  
Genes Encoding ◽  
Metabolizing Enzyme ◽  
The Impact

Abstract BackgroundContext: Methotrexate (MTX) is a cornerstone in the treatment of juvenile idiopathic arthritis (JIA). MTX treatment is commonly associated with nausea. Large inter-individual variation exists in the level of MTX-induced nausea, possibly due to genetic factors. Purpose: To investigate whether MTX-induced nausea was associated with single nucleotide polymorphisms (SNPs) in genes encoding MTX-transporter proteins, a MTX metabolizing enzyme and a nausea receptor.FindingsMethods: Children aged ≥9 years treated with MTX for JIA were eligible. MTX-induced nausea was registered by the children’s completion of a nausea diary (min. 7 days) and the parents’ completion of the MTX intolerance severity score (MISS). The selected SNPs were: SLCO1B1 (rs4149056; rs4149081), SLCO1B3 (rs2117032), SLC19A1 (rs1051266), ABCC2 (rs2273697; rs3740066; rs717620), ABCB1 (rs2032582; rs1045642), MTHFR (rs1801131, rs1801133), HTR3A (rs1062613; rs1985242; rs1176713) and HTR3B (rs1176744). Results: Enrolled were 121 JIA patients (82 girls: 39 boys) with a median age of 13.3 years (IQR: 11.3-15.1). The median MTX dose was 9.7 mg/m2/week (IQR: 9.0-10.9). The median MTX treatment duration prior to enrolment was 340 days (IQR: 142-766). The SNP analysis was available for 119 patients. MTX intolerance was associated with the genotype distribution of rs1801133 (MTHFR) (p= 0.02). There was no additive effect of the minor alleles for any of the selected SNPs, nor any significant haplotype associations. Conclusion Summary: MTX-induced nausea may be influenced by genetic polymorphisms in a MTX metabolizing enzyme (rs1801133; MTHFR). Implications: Further analyses involving inclusion of larger cohorts are needed to understand the impact of SNPs on MTX-induced nausea in JIA.

scholarly journals Single nucleotide polymorphisms associated with methotrexate-induced nausea in juvenile idiopathic arthritis

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Nini Kyvsgaard ◽  
Torben Stamm Mikkelsen ◽  
Thomas D. Als ◽  
Anne Estmann Christensen ◽  
Thomas J. Corydon ◽  
...  
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Single Nucleotide Polymorphisms ◽  
List Type ◽  
Snp Analysis ◽  
Genotype Distribution ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Genes Encoding ◽  
Metabolizing Enzyme ◽  
The Impact

Abstract Background Context: Methotrexate (MTX) is a cornerstone in the treatment of juvenile idiopathic arthritis (JIA). MTX treatment is commonly associated with nausea. Large inter-individual variation exists in the level of MTX-induced nausea, possibly due to genetic factors. Purpose: To investigate whether MTX-induced nausea was associated with single nucleotide polymorphisms (SNPs) in genes encoding MTX-transporter proteins, a MTX metabolizing enzyme and a nausea receptor. Findings Methods: Children aged ≥9 years treated with MTX for JIA were eligible. MTX-induced nausea was registered by the children’s completion of a nausea diary (min. 7 days) and the parents’ completion of the MTX intolerance severity score (MISS). The selected SNPs were: SLCO1B1 (rs4149056; rs4149081), SLCO1B3 (rs2117032), SLC19A1 (rs1051266), ABCC2 (rs2273697; rs3740066; rs717620), ABCB1 (rs2032582; rs1045642), MTHFR (rs1801131, rs1801133), HTR3A (rs1062613; rs1985242; rs1176713) and HTR3B (rs1176744). Result: Enrolled were 121 JIA patients (82 girls: 39 boys) with a median age of 13.3 years (IQR: 11.3–15.1). The median MTX dose was 9.7 mg/m2/week (IQR: 9.0–10.9). The median MTX treatment duration prior to enrolment was 340 days (IQR: 142–766). The SNP analysis was available for 119 patients. MTX intolerance was associated with the genotype distribution of rs1801133 (MTHFR) (p = 0.02). There was no additive effect of the minor alleles for any of the selected SNPs, nor any significant haplotype associations. Conclusion Summary: MTX-induced nausea may be influenced by genetic polymorphisms in a MTX metabolizing enzyme (rs1801133; MTHFR). Implications: Further analyses involving inclusion of larger cohorts are needed to understand the impact of SNPs on MTX-induced nausea in JIA.

scholarly journals Single Nucleotide Polymorphisms Associated with Methotrexate-induced Nausea in Juvenile Idiopathic Arthritis

2020 ◽  
Author(s):  
Nini Kyvsgaard ◽  
Torben Stamm Mikkelsen ◽  
Thomas D. Als ◽  
Anne Estmann Christensen ◽  
Thomas J. Corydon ◽  
...  
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Single Nucleotide Polymorphisms ◽  
Snp Analysis ◽  
Genotype Distribution ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Minor Alleles ◽  
Genes Encoding ◽  
Metabolizing Enzyme ◽  
The Impact

Abstract BackgroundContext: Methotrexate (MTX) is a cornerstone in the treatment of juvenile idiopathic arthritis (JIA). MTX treatment is commonly associated with nausea. Large inter-individual variation exists in the level of MTX-induced nausea, possibly due to genetic factors. Purpose: To investigate whether MTX-induced nausea was associated with single nucleotide polymorphisms (SNPs) in genes encoding MTX-transporter proteins, a MTX metabolizing enzyme and a nausea receptor.FindingsMethods: Children aged ≥9 years treated with MTX for JIA were eligible. MTX-induced nausea was registered by the children’s completion of a nausea diary (min. 7 days) and the parents’ completion of the MTX intolerance severity score (MISS). The selected SNPs were: SLCO1B1 (rs4149056; rs4149081), SLCO1B3 (rs2117032), SLC19A1 (rs1051266), ABCC2 (rs2273697; rs3740066; rs717620), ABCB1 (rs2032582; rs1045642), MTHFR (rs1801131, rs1801133), HTR3A (rs1062613; rs1985242; rs1176713) and HTR3B (rs1176744). Results: Enrolled were 121 JIA patients (82 girls: 39 boys) with a median age of 13.3 years (IQR: 11.3-15.1). The median MTX dose was 9.7 mg/m2/week (IQR: 9.0-10.9). The median MTX treatment duration prior to enrolment was 340 days (IQR: 142-766). The SNP analysis was available for 119 patients. MTX intolerance was associated with the genotype distribution of rs1801133 (MTHFR) (p= 0.02). There was no additive effect of the minor alleles for any of the selected SNPs, nor any significant haplotype associations. Conclusion Summary: MTX-induced nausea may be influenced by genetic polymorphisms in a MTX metabolizing enzyme (rs1801133; MTHFR). Implications: Further analyses involving inclusion of larger cohorts are needed to understand the impact of SNPs on MTX-induced nausea in JIA.

scholarly journals Pharmacogenetic Markers of Treatment Response of Imatinib Mesylate in Chronic Myeloid Leukemia Brazilian Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5458-5458
Author(s):  
Natália M Vieira ◽  
Renata Leite ◽  
Fabíola Reginato ◽  
Marília Zandoná ◽  
Tito Vanelli Costa ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Imatinib Mesylate ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Response To Treatment ◽  
Nucleotide Polymorphisms ◽  
Metabolizing Enzymes ◽  
Single Nucleotide ◽  
Genes Encoding ◽  
Polymerase Chain

Abstract The treatment of chronic myeloid leukemia (CML) was revolutionized by the introduction of imatinib mesylate (IM). However, approximately 20% of patients are non-responsive and interpatient variability in response to IM is still a phenomenon lacking explanation. Single nucleotide polymorphisms (SNPs) located in genes encoding proteins involved in IM pharmacokinetics are potentially involved in the causes of this variation. In this study, we investigated the association of SNPs in the genes encoding IM metabolizing enzymes CYP3A4 (rs35599367 and rs2740574) and CYP3A5 (rs776746) and efflux transporter proteins ABCB1 (rs3213619, rs1128503, rs2032582 and rs1045642), ABCG2 (rs2231142) and ABCC4 (rs9561765) with response to treatment and with IM plasma through levels and hair concentrations. The analyzed sample was constituted of 182 CML patients on IM treatment. DNA samples were genotyped for the nine SNPs using real-time polymerase chain reaction. Hair and plasma trough IM concentrations were measured through liquid chromatography coupled to mass spectrometry methods. Clinical response was defined according to the European Leukemia Net guidelines. The number of responders to standard IM therapy was 104. A trend to a higher frequency of CYP3A4 *22 (rs35599367) allele carriers was observed among responders to IM (12.5 vs. 3.4% of non-responders, P = 0.087), although no significant differences in plasma or hair concentrations between genotypes were found. Pharmacogenetics may become a valuable approach to optimize therapy with IM in CML, but many factors still need to be clarified to make possible its application in clinical practice. Disclosures No relevant conflicts of interest to declare.

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