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1.
Expert Opin Drug Metab Toxicol ; 16(1): 1-9, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31914334

RESUMO

Background: Warfarin acts in heart valve replacement patients to minimize thromboembolic complications. We investigated whether patients can be distinguished based on their genotypes to efficiently and safely administer warfarin therapy after heart valve replacements.Research design and methods: A retrospective analysis was conducted in patients with warfarin therapy who underwent elective heart valve replacements between January 2013 and September 2018. The patients were divided into normal, sensitive, and highly sensitive bins based on their CYP2C9 and VKORC1 genotypes. The primary endpoints were over-anticoagulation and overt bleeding.Results: 375 patients were enrolled, with 65 classified as normal, 281 as sensitive, and 29 as highly sensitive responders. Compared with normal responders, sensitive and highly sensitive responders spent more time on over-anticoagulation in the first 28 (P < 0.001) and 90 (P = 0.001) days; experienced more frequent bleeding events in the first 28 days (P = 0.029; OR, 2.18; 95% CI, 1.15-4.13); required lower warfarin doses to obtain stable INR (P < 0.001); had higher warfarin sensitivity indices (P < 0.001).Conclusion: Predicting evidence have been obtained with CYP2C9 and VKORC1 genotypes in identifying heart valve replacement patients with higher efficient sensitivity and with a higher risk of bleeding and over-anticoagulation.


Assuntos
Anticoagulantes/administração & dosagem , Citocromo P-450 CYP2C9/genética , Hemorragia/induzido quimicamente , Vitamina K Epóxido Redutases/genética , Varfarina/administração & dosagem , Adulto , Idoso , Anticoagulantes/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Genótipo , Implante de Prótese de Valva Cardíaca/métodos , Hemorragia/epidemiologia , Hemorragia/genética , Humanos , Coeficiente Internacional Normatizado , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tromboembolia/prevenção & controle , Varfarina/efeitos adversos
2.
Comput Biol Chem ; 84: 107166, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31785970

RESUMO

Tamoxifen is a prodrug and cytochrome P450 2C9 (CYP2C9) has a significant role in the formation of a therapeutically more potent metabolite (4-hydroxytamoxifen) than tamoxifen. Since CYP2C9 exhibits genetic polymorphism, it may contribute to different phenotypic drug response. Moreover, it may be misleading if the possibility of heterogeneous clinical observations of pharmacogenetic investigations is ignored. Above all, clinical investigation of all the polymorphic variants is beyond the scope of a pharmacogenetic study. Therefore, in order to understand the genotype-phenotype association, it is aimed to study the interatomic interactions of amino acid substitutions in CYP2C9 variants in the presence of tamoxifen. Computational structural biology approach was adopted to study the effect of amino acid substitutions of polymorphic variants of CYP2C9 R144C (*2), I359 L (*3), D360E (*5), R150H (*8), R335W (*11) and L90 P (*13) on the flexibility of the enzyme in the presence of tamoxifen. The mutations were selected based on previously determined associations on genotype and clinical outcome of drugs. Against the above plane, docking of tamoxifen was performed with the crystal structure representing the wild-type form of the enzyme. The docked conformation of tamoxifen was favourable for 4-hydroxylation with the site of metabolism within 5 Šof oxyferrylheme consistent with the drug metabolism pathway of tamoxifen. Further, the effect of amino acid substitutions CYP2C9 variants on the protein flexibility in the presence of tamoxifen in 4-hydroxy orientation was evaluated by molecular dynamics (MD) simulations. Distinct protein flexibility modulations between variants were observed in F/G segment constituting the substrate access/egress channels, helix B' involved with substrate specificity and helix I associated with the holding of substrates. Root Mean Square Fluctuation analysis of the trajectories of variants exhibited fluctuations in F/G segment, B' and I helix. Dominant motions in the structure were identified by performing Principal Component Analysis on trajectories and the porcupine plot depicted displaced F/G segment in variants. Thus, the interatomic interaction study of CYP2C9 variants in the presence of tamoxifen predicts the plausible effect of the investigated variants on the therapeutic outcome of tamoxifen. It is presumed that the observations of the study would be meaningful to understand tamoxifen pharmacogenetics.


Assuntos
Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2C9/metabolismo , Polimorfismo Genético , Tamoxifeno/metabolismo , Substituição de Aminoácidos , Domínio Catalítico , Citocromo P-450 CYP2C9/química , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Maleabilidade , Ligação Proteica , Conformação Proteica em alfa-Hélice , Tamoxifeno/análogos & derivados
3.
Pak J Pharm Sci ; 32(4): 1581-1588, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31608877

RESUMO

Warfarin is administered as a racemic preparation of R- and S-enantiomers. S-warfarin is more potent than R-warfarin, so changes in blood levels of S-warfarin affect the anticoagulant response. This study was carried out to determine the effect of CYP2C9*2 and CYP2C9*3 polymorphisms on S/R warfarin ratio. A single blood sample was collected 12-16 hours after drug administration from 170 stable patients fulfilling the criteria. Genotyping of the CYP2C9 polymorphisms was done by polymerase chain reaction-restriction fragment length polymorphism assay. S- and R-warfarin enantiomers extraction from plasma was accomplished by a validated HPLC method. The concentration of S-warfarin was significantly different among CYP2C9 genotypes (p =0.018) whereas there was no effect on R-warfarin (p =0.134). There was statistically significant effect of different CYP2C9 genotypes on S/R warfarin ratio (p=0.000). It is concluded that CYP2C9 polymorphisms influence CYP2C9 enzymatic activity in turn affecting S-warfari levels but not R-warfarin, thus leading to different S/R warfarin enantiomers ratio among different CYP2C9 genotypes.


Assuntos
Citocromo P-450 CYP2C9/genética , Varfarina/química , Varfarina/farmacocinética , Adolescente , Adulto , Idoso , Anticoagulantes/administração & dosagem , Anticoagulantes/sangue , Anticoagulantes/química , Anticoagulantes/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paquistão , Polimorfismo Genético , Polimorfismo de Fragmento de Restrição , Estereoisomerismo , Varfarina/administração & dosagem , Varfarina/sangue , Adulto Jovem
4.
BMC Med Genet ; 20(1): 148, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477036

RESUMO

BACKGROUND: Single nucleotide polymorphisms (SNPs) in several CYP genes have been associated with altered breast cancer (BC) risk in different populations. Despite this, there is a dearth of information on the roles of these SNPs in Jordanian BC patients. Therefore, this study aims to determine if there is any single nucleotide polymorphism (SNP) within CYP19A1, CYP2C19, CYP2C9, CYP1B1, CYP3A4, and CYP1A2 genes associated with BC in the Jordanian population. In addition, this work investigates the association between selected BC prognostic factors and variants of the aforementioned CYP candidate genes. METHODS: Blood samples were withdrawn from 221 BC patients and 218 healthy volunteers recruited from the Jordanian population. Genomic DNA was withdrawn and, after quantification and quality control, was genotyped using the Sequenom MassARRAY® system (iPLEX GOLD). Statistical analysis was then carried out to assess allelic and genotypic frequencies as well as genetic association between cases and controls. RESULTS: The CYP19A1 SNP rs7176005 (p < 0.0045) and the CYP1A2 SNP rs762551 (p = 0.004) were significantly associated with BC risk. However, no such association was found for the screened SNPs of the CYP2C9, CYP1B1, CYP2C19 and CYP3A4 genes. Regarding the prognostic factors of BC, several of the screened SNPs were associated with different pathological and clinical features. CONCLUSIONS: Certain CYP genes, particularly CYP19A1 and CYP1A2, were associated with BC risk and development in the Jordanian population.


Assuntos
Neoplasias da Mama/genética , Ciclofilinas/genética , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Aromatase/genética , Estudos de Coortes , Citocromo P-450 CYP1A2/genética , Citocromo P-450 CYP1B1/genética , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP3A/genética , Feminino , Genótipo , Humanos , Jordânia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prognóstico , Risco , Adulto Jovem
5.
Forensic Sci Int Genet ; 42: 203-212, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31376648

RESUMO

Drug-induced arrhythmia is an adverse drug reaction that can be potentially fatal since it is mostly related to drug-induced QT prolongation, a known risk factor for Torsade de Pointes and sudden cardiac death (SCD). Several risk factors have been described in association to these drug-induced events, such as preexistent cardiac disease and genetic variation. Our objective was to study the genetic susceptibility in pharmacodynamic and pharmacokinetic pathways underlying suspected drug-induced arrhythmias and sudden unexplained deaths in 32 patients. The genetic component in the pharmacodynamic pathway was studied by analysing 96 genes associated with higher risk of SCD through massive parallel sequencing. Pharmacokinetic-mediated genetic susceptibility was investigated by studying the genes encoding cytochrome P450 enzymes using medium-throughput genotyping. Pharmacodynamic analysis showed three probably pathogenic variants and 45 variants of uncertain significance in 28 patients, several of them previously described in relation to mild or late onset cardiomyopathies. These results suggest that genetic variants in cardiomyopathy genes, in addition to those related with channelopathies, could be relevant to drug-induced cardiotoxicity and contribute to the arrhythmogenic phenotype. Pharmacokinetic analysis showed three patients that could have an altered metabolism of the drugs they received involving CYP2C19 and/or CYP2D6, probably contributing to the arrhythmogenic phenotype. The study of genetic variants in both pharmacodynamic and pharmacokinetic pathways may be a useful strategy to understand the multifactorial mechanism of drug-induced events in both clinical practice and forensic field. However, it is necessary to comprehensively study and evaluate the contribution of the genetic susceptibility to drug-induced cardiotoxicity.


Assuntos
Arritmias Cardíacas/etiologia , Morte Súbita/etiologia , Predisposição Genética para Doença , Variantes Farmacogenômicos , Adolescente , Adulto , Canalopatias/genética , Criança , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP3A/genética , Canal de Potássio ERG1/genética , Feminino , Variação Genética , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Síndrome do QT Longo , Masculino , Pessoa de Meia-Idade , Testes Farmacogenômicos , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Adulto Jovem
6.
Acta Pharm ; 69(3): 399-412, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31259734

RESUMO

The relative contribution of CYP2C9 allelic variants to the pharmacokinetics (PK) of ibuprofen (IBP) enantiomers has been studied extensively, but the potential clinical benefit of pharmacogenetically guided IBP treatment is not evident yet. The role of AKR1D1*36C>T (rs 1872930) allelic variant in interindividual variability of CYP450 mediated drug metabolism was recently elucidated. A total of 27 healthy male subjects, volunteers in IBP single-dose two-way cross-over bioequivalence studies were genotyped for CYP2C9*2, CYP2C9*3 and AKR1D1*36 polymorphisms. The correlation between CYP2C9 and AKR1D1 genetic profile and the PK parameters for S-(+) and R-(-)-IBP was evaluated. Remarkable changes in the PK values pointing to reduced CYP2C9 enzyme activity were detected only in the CYP2C9*2 allelic variant carriers. Statistically significant association between the AKR1D1*36 allele and the increased IBP metabolism (low AUC0-t and 0-∞, high Cltot and short tmax values for both enantiomers) was observed in subjects carrying the CYP2C9 *1/*3 or CYP2C9*1/*1 genotype. The clinical value of concomitant CYP2C9 and AKR1D1 genotyping has to be further verified.


Assuntos
Citocromo P-450 CYP2C9/genética , Ibuprofeno/farmacocinética , Oxirredutases/genética , Polimorfismo Genético/genética , Adolescente , Adulto , Alelos , Estudos Cross-Over , Genótipo , Voluntários Saudáveis , Humanos , Masculino , Taxa de Depuração Metabólica/genética , Pessoa de Meia-Idade , Projetos Piloto , Estereoisomerismo , Adulto Jovem
7.
Croat Med J ; 60(3): 212-220, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31187948

RESUMO

AIM: To investigate the prevalence of common genetic variants that can serve as markers of thrombophilia and warfarin pharmacogenetics in Bosnia and Herzegovina. METHODS: The study was performed between August and October 2017 on 130 healthy unrelated adult volunteers from Bosnian-Herzegovinian population sample. The prevalence of the following genetic variants was determined: F5 c.1601G>A (factor V Leiden), F2 c.*97G>A (factor II or prothrombin mutation), F13A1 (factor XIII) c.103G>T, MTHFR (methylenetetrahydrofolate reductase) c.665C>T and c.1286A>C, as well as PAI-1 (plasminogen activator inhibitor 1) c.-816A>G and c.-844G>A as markers of thrombophilia risk, and *2 and *3 alleles of CYP2C9 (cytochrome P450 2C9) and five variants of VKORC1 (vitamin K epoxide reductase complex subunit 1) as markers of warfarin pharmacogenetics. DNA was isolated from buccal swabs using salting out method, while genotyping was performed using matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry. RESULTS: Minor allele frequencies for two main thrombophilia risk factors, F5 c.1601G>A and F2 c.*97G>A were 0.023 and 0.008, respectively. Combined data for the markers of warfarin pharmacogenetics imply that 57.4% study participants can be expected to metabolize warfarin at an extensive, 40.3% at intermediate, and 2.3% at a poor rate. CONCLUSION: This study reports the first extensive population genetic data for thrombophilia and warfarin pharmacogenetic markers in Bosnia and Herzegovina. Allele frequencies of genetic variants are within the general average for European populations, and their presence implies the necessity of introduction of personalized medicine in warfarin-mediated antithrombotic therapy.


Assuntos
Anticoagulantes/metabolismo , Fatores de Coagulação Sanguínea/genética , Trombofilia/genética , Varfarina/metabolismo , Adolescente , Adulto , Alelos , Biomarcadores , Bósnia e Herzegóvina , Citocromo P-450 CYP2C9/genética , Fator V/genética , Fator XIII/genética , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pessoa de Meia-Idade , Inibidor 1 de Ativador de Plasminogênio/genética , Gravidez , Protrombina/genética , Vitamina K Epóxido Redutases/genética , Adulto Jovem
8.
JAMA Netw Open ; 2(6): e195345, 2019 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-31173123

RESUMO

Importance: Implementation of pharmacogenetic testing to guide drug prescribing has potential to improve drug response and prevent adverse events. Robust data exist for more than 30 gene-drug pairs linking genotype to drug response phenotypes; however, it is unclear which pharmacogenetic tests, if implemented, would provide the greatest utility for a given patient population. Objectives: To project the proportion of veterans in the US Veterans Health Administration (VHA) with actionable pharmacogenetic variants and evaluate how testing might be associated with prescribing decisions. Design, Setting, and Participants: This cross-sectional study included veterans who used national VHA pharmacy services from October 1, 2011, to September 30, 2017. Data analyses began April 26, 2018, and were completed February 6, 2019. Exposures: Receipt of level A drugs based on VHA pharmacy dispensing records. Main Outcomes and Measures: Projected prevalence of actionable pharmacogenetic variants among VHA pharmacy users based on variant frequencies from the 1000 Genomes Project and veteran demographic characteristics; incident number of level A prescriptions, and proportion of new level A drug recipients projected to carry an actionable pharmacogenetic variant. Results: During the study, 7 769 359 veterans (mean [SD] age, 58.1 [17.8] years; 7 021 504 [90.4%] men) used VHA pharmacy services. It was projected that 99% of VHA pharmacy users would carry at least 1 actionable pharmacogenetic variant. Among VHA pharmacy users, 4 259 153 (54.8%) received at least 1 level A drug with 1 188 124 (15.3%) receiving 2 drugs, and 912 189 (11.7%) receiving 3 or more drugs. The most common incident prescriptions during the study were tramadol (923 671 new recipients), simvastatin (533 928 new recipients), citalopram (266 952 new recipients), and warfarin (205 177 new recipients). Gene-drug interactions projected to have substantial clinical impacts in the VHA population include the interaction of SLCO1B1 with simvastatin (1 988 956 veterans [25.6%]), CYP2D6 with tramadol (318 544 veterans [4.1%]), and CYP2C9 or VKORC1 with warfarin (7 163 349 veterans [92.2%]). Conclusions and Relevance: Clinically important pharmacogenetic variants are highly prevalent in the VHA population. Almost all veterans would carry an actionable variant, and more than half of the population had been exposed to a drug affected by these variants. These results suggest that pharmacogenetic testing has the potential to affect pharmacotherapy decisions for commonly prescribed outpatient medications for many veterans.


Assuntos
Frequência do Gene/genética , Variantes Farmacogenômicos/genética , Medicamentos sob Prescrição/uso terapêutico , Saúde dos Veteranos , Estudos Transversais , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2D6/genética , Interações de Medicamentos/genética , Utilização de Instalações e Serviços , Feminino , Genótipo , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Masculino , Pessoa de Meia-Idade , Assistência Farmacêutica/estatística & dados numéricos , Polimorfismo Genético/genética , Prevalência , Sinvastatina/farmacologia , Tramadol/farmacologia , Estados Unidos , United States Department of Veterans Affairs/estatística & dados numéricos , Vitamina K Epóxido Redutases/genética , Varfarina/farmacologia
9.
Drug Metab Pharmacokinet ; 34(3): 201-208, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30992242

RESUMO

The objective of the present study was to investigate the effects of cytochrome b5 (cytb5) on the drug metabolism catalyzed by CYP2C9, CYP2C19 and CYP3A4. Activities of CYP2C9, CYP2C19, and CYP3A4 were determined by using the prototypical substrates tolbutamide, omeprazole and midazolam, respectively. Cytb5 protein and mRNA contents showed large inter-individual variations with 11- and 6-fold range, respectively. All of three P450s showed an increased activity in proportion to the amount of cytb5 expression. Particularly, CYP3A4 showed the strongest correlation between cytb5 protein amount and the activity, followed by CYP2C9 and CYP2C19. The putative splicing variant, c.288G>A (rs7238987) was identified and was screened in 36 liver tissues by direct DNA sequencing. Liver tissues having a splicing variant exhibited unexpected sizes of cytb5 mRNA and a decreased expression tendency of cytb5 protein compared to the wild-type. A decreased activity in the metabolism of the CYP2C19 substrate omeprazole was observed in liver tissues carrying the splicing variant when compared to the wild-type Cytb5 (P < 0.05). The present results propose that different expression of cytb5 can cause variations in CYP mediated drug metabolism, which may explain, at least in part, the inter-individual difference in drug responses in addition to the CYP genetic polymorphisms.


Assuntos
Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP3A/metabolismo , Citocromos b5/genética , Variação Genética , Fígado/metabolismo , Processamento Alternativo , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP3A/genética , Citocromos b5/metabolismo , Humanos , Técnicas In Vitro , Fígado/enzimologia , Midazolam/metabolismo , Omeprazol/metabolismo , Tolbutamida/metabolismo
10.
Genes (Basel) ; 10(4)2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30939847

RESUMO

There is a special interest in the implementation of pharmacogenetics in clinical practice, although there are some barriers that are preventing this integration. A large part of these pharmacogenetic tests are focused on drugs used in oncology and psychiatry fields and for antiviral drugs. However, the scientific evidence is also high for other drugs used in other medical areas, for example, in cardiology. In this article, we discuss the evidence and guidelines currently available on pharmacogenetics for clopidogrel, warfarin, acenocoumarol, and simvastatin and its implementation in daily clinical practice.


Assuntos
Anticoagulantes/efeitos adversos , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/genética , Farmacogenética , Acenocumarol/efeitos adversos , Acenocumarol/uso terapêutico , Anticoagulantes/uso terapêutico , Hidrocarboneto de Aril Hidroxilases/genética , Doenças Cardiovasculares/epidemiologia , Clopidogrel/efeitos adversos , Clopidogrel/uso terapêutico , Citocromo P-450 CYP2C9/genética , Guias como Assunto , Humanos , Medicina de Precisão , Sinvastatina/efeitos adversos , Sinvastatina/uso terapêutico , Varfarina/efeitos adversos , Varfarina/uso terapêutico
11.
Int Arch Allergy Immunol ; 179(3): 173-186, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30943525

RESUMO

BACKGROUND: Self-reported chemical sensitivity (SCS) is characterized by adverse effects due to exposure to low levels of chemical substances. The clinical manifestations of SCS are similar to the allergy, and a high percentage of individuals with both diseases have been found. Various genes, especially genes of importance to the metabolism of xenobiotic compounds, have been associated with SCS. OBJECTIVES: The purpose of this study was to investigate whether allergic individuals with chemical sensitivity differed from allergic patients without chemical sensitivity with regard to the distribution of genotype and phenotype of CYP2C9, CYP2C19, and CYP2D6 polymorphisms. METHODS: A total of 180 patients were enrolled for this study. A questionnaire was employed to collect information on individual chemical sensitivity, while the Skin prick test and the PATCH test were used to verify the presence of an allergic condition against inhalants or contact allergens, respectively. For the evaluation of the CYP2C9, CYP2C19, and CYP2D6 polymorphisms, we used a strategy based on the amplification of the entire gene coupled to direct genomic DNA sequencing analysis. RESULTS: Overall, a total of 15 different CYP2C9, CYP2C19, and CYP2D6 haplotypes were identified in our population. If the 5 CYP2C9 and the 2 CYP2C19 identified alleles correspond to the previously described ones, 4 of the 8 CYP2D6 haplotypes, detected in the study group, present new SNPs combinations. These new suballeles were categorized as CYP2D6*2M Sa-lento Variant 1, CYP2D6*35B Salento Variant 2, CYP2D6*41 Salento Variant 3, and CYP2D6*4P Salento Variant 4 due to the presence of the key SNPs 2,850 C>T, 31G>A, 2,988 G>A, and 1,846 G>A, respectively. When the allergic individuals are divided into 2 groups according to their SCS score, we observed that the distribution of the CYP2D6 phenotypes was significantly different between the 2 groups. CONCLUSIONS: Our idea is that the application of the questionnaire that we have adopted has enabled us to diagnose a degree of chemical sensitivity, which results as comorbid of the allergic disease and in which a condition of poor or intermediate metabolizes for the detrimental CYP2D6 alleles, could represent a discriminant between the chemical sensitivity and the health state.


Assuntos
Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2D6/genética , Hipersensibilidade/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Inquéritos e Questionários , Adulto Jovem
12.
Eur J Clin Pharmacol ; 75(7): 901-911, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30852642

RESUMO

PURPOSE: Large inter-individual differences in warfarin maintenance dose are mostly due to the effect of genetic polymorphisms in multiple genes, including vitamin K epoxide reductase complex 1 (VKORC1), cytochromes P450 2C9 (CYP2C9), and cytochrome P450 4F2 (CYP4F2). Thus, several algorithms for predicting the warfarin dose based on pharmacogenomics data with clinical characteristics have been proposed. Although these algorithms consider these genetic polymorphisms, the formulas have different coefficient values that are critical in this context. In this study, we assessed the mutual validity among these algorithms by specifically considering racial differences. METHODS: Clinical data including actual warfarin dose (AWD) of 125 Japanese patients from our previous study (Eur J Clin Pharmacol 65(11):1097-1103, 2009) were used as registered data that provided patient characteristics, including age, sex, height, weight, and concomitant medications, as well as the genotypes of CYP2C9 and VKORC1. Genotyping for CYP4F2*3 was performed by the PCR method. Five algorithms that included these factors were selected from peer-reviewed articles. The selection covered four populations, Japanese, Chinese, Caucasian, and African-American, and the International Warfarin Pharmacogenetics Consortium (IWPC). RESULTS: For each algorithm, we calculated individual warfarin doses for 125 subjects and statistically evaluated its performance. The algorithm from the IWPC had the statistically highest correlation with the AWD. Importantly, the calculated warfarin dose (CWD) using the algorithm from African-Americans was less correlated with the AWD as compared to those using the other algorithms. The integration of CYP4F2 data into the algorithm did not improve the prediction accuracy. CONCLUSION: The racial difference is a critical factor for warfarin dose predictions based on pharmacogenomics.


Assuntos
Algoritmos , Anticoagulantes/administração & dosagem , Grupo com Ancestrais do Continente Asiático/genética , Citocromo P-450 CYP2C9/genética , Família 4 do Citocromo P450/genética , Vitamina K Epóxido Redutases/genética , Varfarina/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Farmacogenética
13.
Int J Mol Sci ; 20(5)2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30866412

RESUMO

Here, we describe a Dutch family with idiopathic pulmonary fibrosis (IPF). We hypothesized that there might be an association between the presence of Vitamin K epoxide reductase complex 1 (VKORC1) and/or cytochrome P450 2C9 (CYP2C9) variant alleles and the early onset of IPF in the members of this family. VKORC1 (rs9923231 and rs9934438) and CYP2C9 (rs1799853 and rs1057910) were genotyped in this family, which includes a significant number of pulmonary fibrosis patients. In all family members, at least one of the variant alleles tested was present. The presence of the VKORC1 variant alleles in all of the IPF cases and CYP2C9 variants in all but one, which likely leads to a phenotype that is characterized by the early onset and progressive course of IPF. Our findings indicate a role of these allelic variants in (familial) IPF. Therefore, we suggest that the presence of these variants, in association with other pathogenic mutations, should be evaluated during genetic counselling. Our findings might have consequences for the lifestyle of patients with familial IPF in order to prevent the disease from becoming manifest.


Assuntos
Citocromo P-450 CYP2C9/genética , Fibrose Pulmonar Idiopática/genética , Polimorfismo de Nucleotídeo Único , Vitamina K Epóxido Redutases/genética , Adulto , Idade de Início , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Linhagem , Regiões Promotoras Genéticas , Estudos Retrospectivos
14.
Medicine (Baltimore) ; 98(6): e14365, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30732170

RESUMO

Prosthetic Valve Thrombosis (PVT), in spite of the advances in the valve design and the material used, remains a serious complication of mechanical cardiac valve replacement. The factors influencing the development of PVT are: thrombogenicity of the valve, hemodynamics of the transprosthetic blood flow and ineffective anticoagulation. Genetic polymorphism of the genes VKORC1 (-1639 G > A and 1173 C > T), CYP2C9 (*2 & *3 alleles) and CYP4F2 (1347 G > A) are known to influence the anticoagulant dose-effect response. Since there has not been any earlier study on the direct influence of gene polymorphism on the development of PVT, we investigated into this association.Genotyping for the genes VKORC1, CYP2C9 and CYP4F2 was carried out by conventional PCR-RFLP method for 91 consecutive PVT patients. Subjects of our earlier study served as controls (n = 136).Female patients and patients with smaller prosthetic valve size were more prone to developing PVT (68%, n = 62). Patients bearing A allele of CYP4F2 1347 G > A polymorphism exhibited a fivefold increased risk of PVT (OR = 5.022 (1.39-18.04), P = .013). G allele of VKORC1 when analyzed in combination of genotypes showed a fourteen fold increased risk for developing PVT (OR = 14.25 (5.52-36.77), P = 0.001). CYP2C9 (*2&*3) gene polymorphism did not show any significant association with PVT (OR = 1.54 (0.128 - 18.82), P = .731).Patients bearing A allele of CYP4F2 showed an increased risk of developing PVT in our case - control study.


Assuntos
Citocromo P-450 CYP2C9/genética , Família 4 do Citocromo P450/genética , Próteses Valvulares Cardíacas/efeitos adversos , Trombose/genética , Vitamina K Epóxido Redutases/genética , Adolescente , Adulto , Idoso , Alelos , Anticorpos Antifosfolipídeos/sangue , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Fatores Sexuais , Adulto Jovem
15.
Mol Biol Rep ; 46(2): 1825-1833, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30712247

RESUMO

It was aimed to underline the importance and explain the meaning of genetic testing in warfarin dosing and investigate and evaluate the contributions of the CYP2C9, VKORC1, and CYP4F2 variants in a Turkish population. Two hundred patients were genotyped for CYP2C9 (rs1799853, rs1057910 and rs56165452), VKORC1 (rs9934438, rs8050894, rs9923231, rs7294 and rs2359612) and CYP4F2 (rs2108622), yet, only 127 patients were found suitable for further evaluation in terms of their personal response to warfarin due to long term usage and available INR and dose usage information. The DNA sequences were determined by the ABI PRISM 3100 Genetic Analyzer to 3130xl System (Applied Biosystems, Foster City, California). Warfarin dose application suggestions by warfaringdosing.org, FDA and MayoClinic were followed. Dose requirements in the Turkish population were found higher than the suggested doses by warfarindosing.org. The multivariate logistic regression analysis reveals the utilization of VCORC1 genetic evaluation is valuable in warfarin dosing (low and moderate vs. high) in this study (p < 0.001). The present study provides findings for clinicians to adapt the genetic data to the daily practice. We observed that the VKORC1 variant showed a more potent impact in warfarin dosing in this study.


Assuntos
Citocromo P-450 CYP2C9/metabolismo , Família 4 do Citocromo P450/metabolismo , Vitamina K Epóxido Redutases/metabolismo , Varfarina/farmacologia , Adulto , Idoso , Biomarcadores Farmacológicos , Citocromo P-450 CYP2C9/genética , Família 4 do Citocromo P450/genética , Relação Dose-Resposta a Droga , Feminino , Frequência do Gene , Variação Genética/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Farmacogenética , Polimorfismo de Nucleotídeo Único , Turquia , Vitamina K Epóxido Redutases/genética , Varfarina/administração & dosagem
16.
Clin Pharmacol Ther ; 105(2): 411-416, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30652304

RESUMO

The US Food and Drug Administration (FDA) reference-scaled average bioequivalence approach scales the bioequivalence (BE) limits of narrow therapeutic index drugs (NTIDs) to the intrasubject or within-subject variability (WSV) of the reference-listed drug. A clinical study was conducted to evaluate the WSV of warfarin (Coumadin), 10 mg, administered to 10 healthy volunteers exhibiting similar cytochrome P450 2C9 and vitamin K epoxide reductase alleles on 3 study days. Individual intrasubject coefficients of variation for maximum plasma concentration and area under the curve (0-72 hour) ranged from 3.7-15% and from 4.3-16.2%, respectively (R-warfarin) and from 5.4-19.1% and from 2.5-11.9%, respectively (S-warfarin). Two BE tests were performed on a WSV distribution obtained by bootstrapping 1,000 replicates of the clinical data, yielding passing rates of 95-97% for the mean comparison and 84-87% for the variability comparison. The variability comparison passing rate was lower than expected for an NTID product tested against itself, but it may provide further assurance of BE.


Assuntos
Tratamento Farmacológico , Adulto , Anticoagulantes/efeitos adversos , Anticoagulantes/farmacocinética , Área Sob a Curva , Estudos Cross-Over , Citocromo P-450 CYP2C9/genética , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Estereoisomerismo , Equivalência Terapêutica , Vitamina K Epóxido Redutases/genética , Varfarina/efeitos adversos , Varfarina/farmacocinética
17.
Hepatol Int ; 13(2): 214-221, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30617764

RESUMO

INTRODUCTION: Anticoagulation is universally recommended in Budd-Chiari syndrome [BCS]. Vitamin K epoxide reductase complex 1 (VKORC1) and CYP2C9 are involved in the metabolism of warfarin. The present study was done to assess whether these mutations are associated with the risk of bleeding in patients with BCS receiving warfarin. PATIENTS AND METHODS: Patients diagnosed with BCS underwent genotyping for three single nucleotide polymorphisms [SNPs]-two for the CYP2C9 and one for the VKORC1 haplotype. The patients were followed up for at least 12 months and all bleeding episodes were recorded. Patients with and without mutations were compared for bleeding complications and a crude odds ratio [crude OR] was derived for the association between bleeding and presence or absence of mutant alleles. RESULTS: Eighty patients [mean (SD) age 27.47 (8.93) years, 35 male] with BCS underwent genetic testing. 37/80 (46.2%) patients had mutation of CYP2C9 and/or VKORC1; 22/80 (27.5%) had either of the mutant alleles of CYP2C9 and, similarly, 22/80 (27.5%) had the VKORC mutation. Over a median follow-up of 20 (range 12-96) months, 21/80 (26.3%) patients had bleeding complications. Patients with mutant SNPs had a higher risk of bleeding than those without [14/37 vs. 7/43, p = 0.04, crude OR (95% CI) 3.13 (1.1-8.9)]. CONCLUSION: The presence of mutations in VKORC1 or CYP2C9 is associated with increased risk of bleeding in patients with BCS on warfarin. Such patients with SNPs of CY2C9 or VKORC1 haplotype should be monitored intensively while receiving warfarin.


Assuntos
Anticoagulantes/efeitos adversos , Síndrome de Budd-Chiari/tratamento farmacológico , Citocromo P-450 CYP2C9/genética , Hemorragia/genética , Vitamina K Epóxido Redutases/genética , Varfarina/efeitos adversos , Adolescente , Adulto , Alelos , Síndrome de Budd-Chiari/etiologia , Feminino , Haplótipos , Hemorragia/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único , Índice de Gravidade de Doença , Adulto Jovem
18.
Leuk Lymphoma ; 60(1): 216-221, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29741432

RESUMO

Imatinib has been successful in the management of chronic myeloid leukemia (CML) but some patients experience adverse reactions or develop resistance to its use. The roles of some polymorphisms in genes encoding enzymes critical for the biotransformation of imatinib have been previously examined. This study, hence, evaluated some other unstudied functionally significant polymorphisms in CYP1A2, CYP2C8, CYP2C9, and CYP3A5. Trough imatinib blood levels and genotypes were determined in 42 CML patients by an HPLC-UV technique and a Sequenom iPLEX assay, respectively. Statistical analysis of the influence of genetic polymorphisms on standardized trough level detected no significant relationship. However, higher trough levels were observed in two homozygous carriers of CYP2C8*2 while diminished imatinib levels were seen in two homozygous carriers of CYP3A5*7. The study findings suggest that polymorphisms in drug metabolizing enzymes may be significant for imatinib therapy only in instances where all copies of the relevant studied genes are functionally impaired.


Assuntos
Antineoplásicos/farmacocinética , Variação Biológica da População/genética , Mesilato de Imatinib/farmacocinética , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Adolescente , Adulto , Idoso , Antineoplásicos/uso terapêutico , Biotransformação , Citocromo P-450 CYP1A2/genética , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP2C8/genética , Citocromo P-450 CYP2C8/metabolismo , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Feminino , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mieloide de Fase Crônica/genética , Masculino , Pessoa de Meia-Idade , Nigéria , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Adulto Jovem
19.
IEEE J Biomed Health Inform ; 23(1): 395-406, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29993619

RESUMO

An evolutionary ensemble modeling (EEM) method is developed to improve the accuracy of warfarin dose prediction. In EEM, genetic programming (GP) evolves diverse base models, and the genetic algorithm optimizes the parameters of the GP. The EEM model is assembled by using the prepared base models through a technique called "bagging." In the experiment, a dataset of 289 Chinese patients, which was provided by the First Affiliated Hospital of Soochow University, is used for training, validation, and testing. The EEM model with selected feature groups is benchmarked with four machine-learning methods and three conventional regression models. Results show that the EEM model with the M2+G group, namely age, height, weight, gender, CYP2C9, VKORC1, and amiodarone, presents the largest coefficients of determination (R2), the highest percentage of the predicted dose within 20% of the actual dose (20%-p), the smallest mean absolute error, mean squared error, and root-mean-squared error on the test set, and the least decrease in R2 from the training set to the test set. In conclusion, the EEM method with M2+G delivers superior performance and can, therefore, be a suitable prediction model of warfarin dose for clinical applications.


Assuntos
Algoritmos , Modelos Estatísticos , Farmacogenética/métodos , Varfarina/administração & dosagem , Adulto , Idoso , Citocromo P-450 CYP2C9/genética , Bases de Dados Factuais , Feminino , Humanos , Aprendizado de Máquina , Masculino , Informática Médica , Pessoa de Meia-Idade , Estudos Retrospectivos , Varfarina/uso terapêutico , Adulto Jovem
20.
Eur J Drug Metab Pharmacokinet ; 44(1): 83-89, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30159654

RESUMO

BACKGROUND AND OBJECTIVE: Cytochrome P450 (CYP) 2C9 catalyzes the biotransformation of indomethacin to its inactive metabolite O-desmethylindomethacin (DMI). The aim of this work was to determine the effect of CYP2C9 polymorphisms on indomethacin metabolism in pregnant women. METHODS: Plasma concentrations of indomethacin and DMI at steady state were analyzed with a validated LC-MS/MS method. DNA was isolated from subject blood and buccal smear samples. Subjects were grouped by genotype for comparisons of pharmacokinetic parameters. RESULTS: For subjects with the *1/*2 genotype, the mean steady-state apparent oral clearance (CL/Fss) of indomethacin was 13.5 ± 7.7 L/h (n = 4) and the mean metabolic ratio (AUCDMI/AUCindomethacin) was 0.291 ± 0.133. For subjects with the *1/*1 genotype, these values were 12.4 ± 2.7 L/h and 0.221 ± 0.078, respectively (n = 14). Of note, we identified one subject who was a carrier of both the *3 and *4 alleles, resulting in an amino acid change (I359P) which has not been reported previously. This subject had a metabolic ratio of 0.390 and a CL/Fss of indomethacin (24.3 L/h) that was nearly double the wild-type clearance. CONCLUSION: Although our results are limited by sample size and are not statistically significant, these data suggest that certain genetic polymorphisms of CYP2C9 may lead to an increased metabolic ratio and an increase in the clearance of indomethacin. More data are needed to assess the impact of CYP2C9 genotype on the effectiveness of indomethacin as a tocolytic agent.


Assuntos
Anti-Inflamatórios não Esteroides/sangue , Citocromo P-450 CYP2C9/genética , Indometacina/sangue , Polimorfismo Genético/genética , Gravidez/sangue , Adolescente , Adulto , Anti-Inflamatórios não Esteroides/farmacocinética , Feminino , Humanos , Indometacina/farmacocinética , Gravidez/efeitos dos fármacos , Adulto Jovem
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