RESUMO
Selective serotonin reuptake inhibitors (SSRIs) are primary treatment options for major depressive and anxiety disorders. CYP2D6 and CYP2C19 polymorphisms can influence the metabolism of SSRIs, thereby affecting drug efficacy and safety. We summarize evidence from the published literature supporting these associations and provide dosing recommendations for fluvoxamine, paroxetine, citalopram, escitalopram, and sertraline based on CYP2D6 and/or CYP2C19 genotype (updates at www.pharmgkb.org).
Assuntos
Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2D6/genética , Cálculos da Dosagem de Medicamento , Farmacogenética/normas , Polimorfismo Genético , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Biotransformação , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Genótipo , Humanos , Segurança do Paciente , Fenótipo , Medição de Risco , Fatores de Risco , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Inibidores Seletivos de Recaptação de Serotonina/farmacocinéticaRESUMO
The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for HLA-B Genotype and Abacavir Dosing were originally published in April 2012. We reviewed recent literature and concluded that none of the evidence would change the therapeutic recommendations in the original guideline; therefore, the original publication remains clinically current. However, we have updated the Supplementary Material online and included additional resources for applying CPIC guidelines to the electronic health record. Up-to-date information can be found at PharmGKB (http://www.pharmgkb.org).
Assuntos
Fármacos Anti-HIV/administração & dosagem , Didesoxinucleosídeos/administração & dosagem , Antígenos HLA-B/genética , Registros Eletrônicos de Saúde , Genótipo , Humanos , FarmacogenéticaRESUMO
Polymorphisms in CYP2D6 and CYP2C19 affect the efficacy and safety of tricyclics, with some drugs being affected by CYP2D6 only, and others by both polymorphic enzymes. Amitriptyline, clomipramine, doxepin, imipramine, and trimipramine are demethylated by CYP2C19 to pharmacologically active metabolites. These drugs and their metabolites, along with desipramine and nortriptyline, undergo hydroxylation by CYP2D6 to less active metabolites. Evidence from published literature is presented for CYP2D6 and CYP2C19 genotype-directed dosing of tricyclic antidepressants.
Assuntos
Antidepressivos Tricíclicos/administração & dosagem , Hidrocarboneto de Aril Hidroxilases/genética , Citocromo P-450 CYP2D6/genética , Antidepressivos Tricíclicos/efeitos adversos , Antidepressivos Tricíclicos/farmacocinética , Citocromo P-450 CYP2C19 , Relação Dose-Resposta a Droga , Genótipo , Humanos , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/fisiopatologia , Farmacogenética , Polimorfismo GenéticoRESUMO
Research on genes and medications has advanced our understanding of the genetic basis of individual drug responses. The aim of pharmacogenomics is to develop strategies for individualizing therapy for patients, in order to optimize outcome through knowledge of the variability of the human genome and its influence on drug response. Pharmacogenomics research is translational in nature and ranges from discovery of genotype-phenotype relationships to clinical trials that can provide proof of clinical impact. Advances in pharmacogenomics offer significant potential for subsequent clinical application in individual patients; however, the translation of pharmacogenomics research findings into clinical practice has been slow. Key components to successful clinical implementation of pharmacogenomics will include consistent interpretation of pharmacogenomics test results, availability of clinical guidelines for prescribing on the basis of test results, and knowledge-based decision support systems.
Assuntos
Farmacogenética/métodos , Medicina de Precisão/métodos , Pesquisa Translacional Biomédica/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Estudo de Associação Genômica Ampla/métodos , Estudo de Associação Genômica Ampla/tendências , Humanos , Preparações Farmacêuticas/administração & dosagem , Farmacogenética/tendências , Medicina de Precisão/tendências , Pesquisa Translacional Biomédica/tendênciasRESUMO
There are several hurdles to the clinical implementation of pharmacogenetics. One approach is to employ pre-prescription genotyping, involving interrogation of multiple pharmacogenetic variants using a high-throughput platform. We compared the performance of the Drug Metabolizing Enzymes and Transporters (DMET) Plus array (1,931 variants in 225 genes) with that of orthogonal genotyping methods in 220 pediatric patients. A total of 1,692 variants had call rates >98% and were in Hardy-Weinberg equilibrium. Of these, 259 were genotyped by at least one independent method, and a total of 19,942 single-nucleotide polymorphism (SNP)-patient sample pairs were evaluated. The concordance rate was 99.9%, with only 28 genotype discordances observed. For the genes deemed most likely to be clinically relevant (TPMT, CYP2D6, CYP2C19, CYP2C9, VKORC1, DPYD, UGT1A1, and SLCO1B1), a total of 3,799 SNP-patient sample pairs were evaluable and had a concordance rate of 99.96%. We conclude that the DMET Plus array performs well with primary patient samples, with the results in good concordance with those of several lower-throughput genotyping methods.
Assuntos
Técnicas de Genotipagem/métodos , Sistema Enzimático do Citocromo P-450/genética , Feminino , Genes/genética , Genótipo , Humanos , Inativação Metabólica/genética , Masculino , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Polimorfismo de Nucleotídeo Único/genética , População Branca/genéticaAssuntos
Antidepressivos Tricíclicos , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2D6/genética , Técnicas de Genotipagem/métodos , Conduta do Tratamento Medicamentoso/normas , Variantes Farmacogenômicos/genética , Antidepressivos Tricíclicos/efeitos adversos , Antidepressivos Tricíclicos/farmacocinética , Relação Dose-Resposta a Droga , Humanos , Polimorfismo Genético , Resultado do TratamentoAssuntos
Pesquisa Biomédica/organização & administração , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Medicina Baseada em Evidências/organização & administração , Comunicação Interdisciplinar , National Institutes of Health (U.S.)/organização & administração , Farmacogenética/organização & administração , Variantes Farmacogenômicos/genética , Animais , Pesquisa Biomédica/normas , Consenso , Comportamento Cooperativo , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Medicina Baseada em Evidências/normas , Genótipo , Humanos , Farmacogenética/normas , Fenótipo , Guias de Prática Clínica como Assunto , Medição de Risco , Estados UnidosRESUMO
The filamentous fungus Aspergillus nidulans contains a cluster of 25 genes that encode enzymes required to synthesize a toxic and carcinogenic secondary metabolite called sterigmatocystin (ST), a precursor of the better known fungal toxin aflatoxin (AF). One ST Cluster (stc) gene, aflR, functions as a pathway-specific transcriptional regulator for activation of other genes in the ST pathway. However, the mechanisms controlling activation of aflR and synthesis of ST and AF are not understood. Here we show that one important level for control of stc gene expression requires genes that were first identified as early acting regulators of asexual sporulation. Specifically, we found that loss-of-function mutations in flbA, which encodes a RGS domain protein, or dominant activating mutations in fadA, which encodes the alpha subunit of a heterotrimeric G protein, block both ST production and asexual sporulation. Moreover, overexpression of flbA or dominant interfering fadA mutations cause precocious stc gene expression and ST accumulation, as well as unscheduled sporulation. The requirement for flbA in sporulation and ST production could be suppressed by loss-of-function fadA mutations. The ability of flbA to activate stc gene expression was dependent upon another early acting developmental regulator, fluG, and AflR, the stc gene-specific transcription factor. These results are consistent with a model in which both asexual sporulation and ST production require inactivation of proliferative growth through inhibition of FadA-dependent signaling. This regulatory mechanism is conserved in AF-producing fungi and could therefore provide a means of controlling AF contamination.