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1.
Pediatr Obes ; 14(1)2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30257076

RESUMO

BACKGROUND: Children with obesity are more likely to suffer gastroesophageal reflux disease, requiring acid-suppression therapy with proton pump inhibitors (PPIs) and no guidelines regarding dosing. OBJECTIVE: To prospectively evaluate lean-body-weight-based (LBW) dosing of the PPI pantoprazole for children with and without obesity. METHODS: Methods: Sixty-two children (6-17 years) received a one-time oral dose of liquid pantoprazole (1.2 mg kg-1 LBW). Plasma pantoprazole concentrations were measured at 10 time points over 8 h and pharmacokinetic (PK) profiles generated using non-compartmental techniques, in order to compare PK parameters of interest between children with and without obesity, while accounting for CYP2C19 genotype. RESULTS: Adjusted for milligram-per-kilogram total body weight (TBW) pantoprazole received, apparent drug clearance (CL/F) was reduced 50% in children with vs. without obesity (p=0.03). LBW-based dosing compensated for this reduction in CL/F (p = 0.15). CONCLUSION: To achieve comparable systemic PPI exposures for children with and without obesity, we recommend using LBW, rather than TBW-based dosing for pantoprazole.


Assuntos
Peso Corporal/efeitos dos fármacos , Refluxo Gastroesofágico/tratamento farmacológico , Pantoprazol/administração & dosagem , Obesidade Infantil/complicações , Inibidores da Bomba de Prótons/administração & dosagem , Adolescente , Criança , Citocromo P-450 CYP2C19/genética , Cálculos da Dosagem de Medicamento , Feminino , Seguimentos , Refluxo Gastroesofágico/etiologia , Genótipo , Humanos , Masculino , Pantoprazol/farmacocinética , Obesidade Infantil/tratamento farmacológico , Estudos Prospectivos , Inibidores da Bomba de Prótons/farmacocinética
5.
Clin Pharmacol Ther ; 100(4): 362-70, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27301780

RESUMO

Protein expression of major hepatic uptake and efflux drug transporters in human pediatric (n = 69) and adult (n = 41) livers was quantified by liquid chromatography / tandem mass spectroscopy (LC-MS/MS). Transporter protein expression of OCT1, OATP1B3, P-gp, and MRP3 was age-dependent. Particularly, significant differences were observed in transporter expression (P < 0.05) between the following age groups: neonates vs. adults (OCT1, OATP1B3, P-gp), neonates or infants vs. adolescents and/or adults (OCT1, OATP1B3, and P-gp), infants vs. children (OATP1B3 and P-gp), and adolescents vs. adults (MRP3). OCT1 showed the largest increase, of almost 5-fold, in protein expression with age. Ontogenic expression of OATP1B1 was confounded by genotype and was revealed only in livers harboring SLCO1B1*1A/*1A. In livers >1 year, tissues harboring SLCO1B1*14/*1A showed 2.5-fold higher (P < 0.05) protein expression than SLCO1B1*15/*1A. Integration of these ontogeny data in physiologically based pharmacokinetic (PBPK) models will be a crucial step in predicting hepatic drug disposition in children.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/biossíntese , Envelhecimento/metabolismo , Transportador 1 de Ânion Orgânico Específico do Fígado/biossíntese , Fígado/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/biossíntese , Transportadores de Ânions Orgânicos Sódio-Independentes/biossíntese , Transportador 1 de Cátions Orgânicos/biossíntese , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Adolescente , Criança , Pré-Escolar , Genótipo , Humanos , Lactente , Recém-Nascido , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Proteína 2 Associada à Farmacorresistência Múltipla , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único/genética , Proteômica , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto
6.
Pharmacogenomics J ; 16(6): 566-572, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-26503815

RESUMO

The relationship between genetic variation in CYP2D6 and variable drug response represents a potentially powerful pharmacogenetic tool. However, little is known regarding this relationship in the genetically diverse South African population. The aim was therefore to evaluate the relationship between predicted and measured CYP2D6 phenotype. An XL-PCR+Sequencing approach was used to determine CYP2D6 genotype in 100 healthy volunteers and phenotype was predicted using activity scores. With dextromethorphan as the probe drug, metabolic ratios served as a surrogate measure of in vivo CYP2D6 activity. Three-hour plasma metabolic ratios of dextrorphan/dextromethorphan were measured simultaneously using semi-automated online solid phase extraction coupled with tandem mass spectrometry. Partial adaptation of the activity score system demonstrated a strong association between genotype and phenotype, as illustrated by a kappa value of 0.792, inter-rater discrepancy of 0.051 and sensitivity of 72.7%. Predicted phenotype frequencies using the modified activity score were 1.3% for poor metabolisers (PM), 7.6% for intermediate metabolisers (IM) and 87.3% for extensive metabolisers (EM). Measured phenotype frequencies were 1.3% for PM, 13.9% for IM and 84.8% for EM. Comprehensive CYP2D6 genotyping reliably predicts CYP2D6 activity in this South African cohort and can be utilised as a valuable pharmacogenetic tool.


Assuntos
Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Dextrometorfano/metabolismo , Farmacogenética , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Adulto , Povo Asiático/genética , Biotransformação/genética , População Negra/genética , Estudos de Coortes , Dextrometorfano/sangue , Dextrorfano/metabolismo , Feminino , Frequência do Gene , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Testes Farmacogenômicos/métodos , Fenótipo , Reação em Cadeia da Polimerase , África do Sul , Espectrometria de Massas em Tandem , População Branca/genética , Adulto Jovem
7.
Clin Pharmacol Ther ; 99(2): 172-85, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26479518

RESUMO

This article provides nomenclature recommendations developed by an international workgroup to increase transparency and standardization of pharmacogenetic (PGx) result reporting. Presently, sequence variants identified by PGx tests are described using different nomenclature systems. In addition, PGx analysis may detect different sets of variants for each gene, which can affect interpretation of results. This practice has caused confusion and may thereby impede the adoption of clinical PGx testing. Standardization is critical to move PGx forward.


Assuntos
Alelos , Testes Genéticos/normas , Farmacogenética/normas , Terminologia como Assunto , Genes , Testes Genéticos/tendências , Variação Genética , Humanos , Farmacogenética/tendências , Medicina de Precisão
8.
Clin Pharmacol Ther ; 99(6): 642-50, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26660002

RESUMO

The effect of CYP2D6 genotype on the dose-exposure relationship for atomoxetine has not been well characterized in children. Children 6-17 years of age diagnosed with attention-deficit hyperactivity disorder (ADHD) were stratified by CYP2D6 genotype into groups with 0 (poor metabolizers [PMs], n = 4), 0.5 (intermediate metabolizers [IMs], n = 3), one (extensive metabolizer [EM]1, n = 8) or two (EM2, n = 8) functional alleles and administered a single 0.5 mg/kg oral dose of atomoxetine (ATX). Plasma and urine samples were collected for 24 (IM, EM1, and EM2) or 72 hours (PMs). Dose-corrected ATX systemic exposure (area under the curve [AUC]0-∞ ) varied 29.6-fold across the study cohort, ranging from 4.4 ± 2.7 µM*h in EM2s to 5.8 ± 1.7 µM*h, 16.3 ± 2.9 µM*h, and 50.2 ± 7.3 µM*h in EM1s, IMs, and PMs, respectively (P < 0.0001). Simulated steady state profiles at the maximum US Food and Drug Administration (FDA)-recommended dose suggest that most patients are unlikely to attain adequate ATX exposures. These data support the need for individualized dosing strategies for more effective use of the medication.


Assuntos
Inibidores da Captação Adrenérgica/farmacocinética , Cloridrato de Atomoxetina/farmacocinética , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Citocromo P-450 CYP2D6/genética , Adolescente , Inibidores da Captação Adrenérgica/administração & dosagem , Inibidores da Captação Adrenérgica/uso terapêutico , Alelos , Área Sob a Curva , Cloridrato de Atomoxetina/administração & dosagem , Cloridrato de Atomoxetina/uso terapêutico , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Biotransformação , Criança , Estudos de Coortes , Citocromo P-450 CYP2C19/genética , Feminino , Genótipo , Humanos , Estudos Longitudinais , Masculino , Medicina de Precisão
9.
Clin Pharmacol Ther ; 98(2): 127-34, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25974703

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/farmacocinética
10.
Clin Pharmacol Ther ; 98(2): 205-15, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25968989

RESUMO

Developmental changes in the liver can significantly impact drug disposition. Due to the emergence of microRNAs (miRNAs) as important regulators of drug disposition gene expression, we studied age-dependent changes in miRNA expression. Expression of 533 miRNAs was measured in 90 human liver tissues (fetal, pediatric [1-17 years], and adult [28-80 years]; n = 30 each). In all, 114 miRNAs were upregulated and 72 were downregulated from fetal to pediatric, and 2 and 3, respectively, from pediatric to adult. Among the developmentally changing miRNAs, 99 miRNA-mRNA interactions were predicted or experimentally validated (e.g., hsa-miR-125b-5p-CYP1A1; hsa-miR-34a-5p-HNF4A). In human liver samples (n = 10 each), analyzed by RNA-sequencing, significant negative correlations were observed between the expression of >1,000 miRNAs and mRNAs of drug disposition and regulatory genes. Our data suggest a mechanism for the marked changes in hepatic gene expression between the fetal and pediatric developmental periods, and support a role for these age-dependent miRNAs in regulating drug disposition.


Assuntos
Envelhecimento/genética , Fígado/metabolismo , MicroRNAs/genética , Farmacogenética , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/metabolismo , Biotransformação/genética , Criança , Pré-Escolar , Análise por Conglomerados , Biologia Computacional , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica no Desenvolvimento , Regulação Enzimológica da Expressão Gênica , Humanos , Lactente , MicroRNAs/metabolismo , Pessoa de Meia-Idade
11.
Clin Pharmacol Ther ; 95(4): 376-82, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24458010

RESUMO

Codeine is bioactivated to morphine, a strong opioid agonist, by the hepatic cytochrome P450 2D6 (CYP2D6); hence, the efficacy and safety of codeine are governed by CYP2D6 activity. Polymorphisms are a major cause of CYP2D6 variability. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for codeine based on CYP2D6 genotype. This document is an update to the 2012 Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for CYP2D6 genotype and codeine therapy.


Assuntos
Analgésicos Opioides/farmacocinética , Codeína/farmacocinética , Citocromo P-450 CYP2D6/genética , Farmacogenética , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Codeína/administração & dosagem , Codeína/efeitos adversos , Citocromo P-450 CYP2D6/metabolismo , Testes Genéticos , Genótipo , Humanos , Morfina/metabolismo , Polimorfismo Genético
12.
Clin Toxicol (Phila) ; 51(7): 540-4, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23855716

RESUMO

BACKGROUND: Methamphetamine (METH) has been associated with a dilated cardiomyopathy. The first and rate-limiting step of metabolism is dependent on the polymorphic enzyme CYP2D6. OBJECTIVES: To evaluate if polymorphisms in CYP2D6 can be associated with the development of a methamphetamine-induced cardiomyopathy. METHODS: We performed a prospective case-control pilot study. Cases were defined by a urinary drug screen positive for amphetamine and evidence of heart failure by beta natriuretic peptide (BNP) greater than 300 pg/ml and symptoms of heart failure. Controls were defined with urinary drug screens positive for amphetamines but without evidence of heart failure defined by a BNP lesser than 300 pg/ml or symptoms of heart failure. Exclusion criteria were less than 18 years or greater than 60 years of age, urinary toxicology screen positive for additional stimulants, known coronary artery disease (CAD) defined by greater than 50% stenosis on catheterization or previous myocardial infarction, known cardiomyopathy of alternative etiology or inability to provide consent. Patients underwent gas chromatography confirmation-mass spectroscopy for methamphetamine, genotyping of CYP2D6, limited echocardiography, and participated in a modified 2007 National Survey of Drug Use and Health Stimulant Survey. Genotype results were analyzed with traditional classifications and "Activity Scores". RESULTS: Fifty-six patients completed the study with 19 cases and 37 controls. There was no statistically significant difference in days of use in a month, age, gender, or ethnicity between cases and controls. While not statistically significant, age and days of use did trend higher in cases. CYP2D6 genotype demonstrated that the lower the activity score/poor metabolizer group had less heart failure than extensive metabolizers/higher activity score. However, it did not reach statistical significance. When adjusting for higher days of use, extensive metabolizers had the highest odds of developing a dilated cardiomyopathy. (OR: 2.33, 95% CI: 0.54-10.13). Echo findings in all cases showed reduced ejection fractions with a mean of 18.6% (range: 10-35%) and 70% had a dilated cardiomyopathy. No cardiomyopathies were seen in the controls. Mean ejection fraction was 56.75% (range: 45-70%). The odds ratio of having a dilated cardiomyopathy in extensive metabolizers was 1.62 (95% CI: 0.47-5.5). CONCLUSION: Our study demonstrates a trend that individuals with decreased metabolic activity were less likely to develop heart failure. While not statistically significant, a signal is present that extensive metabolizers may be at increased risk for the development of a cardiomyopathy.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/complicações , Cardiomiopatia Dilatada/genética , Estimulantes do Sistema Nervoso Central/efeitos adversos , Citocromo P-450 CYP2D6/genética , Insuficiência Cardíaca/genética , Metanfetamina/efeitos adversos , Polimorfismo Genético , Adulto , Transtornos Relacionados ao Uso de Anfetaminas/diagnóstico , Biomarcadores/sangue , Cardiomiopatia Dilatada/sangue , Cardiomiopatia Dilatada/induzido quimicamente , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/enzimologia , Estudos de Casos e Controles , Estimulantes do Sistema Nervoso Central/metabolismo , Distribuição de Qui-Quadrado , Citocromo P-450 CYP2D6/metabolismo , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Predisposição Genética para Doença , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/enzimologia , Humanos , Modelos Logísticos , Masculino , Metanfetamina/metabolismo , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Razão de Chances , Fenótipo , Projetos Piloto , Valor Preditivo dos Testes , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Detecção do Abuso de Substâncias
13.
Clin Pharmacol Ther ; 93(5): 402-8, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23486447

RESUMO

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 Genético
14.
Clin Pharmacol Ther ; 91(2): 321-6, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22205192

RESUMO

Codeine is bioactivated to morphine, a strong opioid agonist, by the hepatic cytochrome P450 2D6 (CYP2D6); hence, the efficacy and safety of codeine as an analgesic are governed by CYP2D6 polymorphisms. Codeine has little therapeutic effect in patients who are CYP2D6 poor metabolizers, whereas the risk of morphine toxicity is higher in ultrarapid metabolizers. The purpose of this guideline (periodically updated at http://www.pharmgkb.org) is to provide information relating to the interpretation of CYP2D6 genotype test results to guide the dosing of codeine.


Assuntos
Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/farmacocinética , Codeína/administração & dosagem , Codeína/farmacocinética , Citocromo P-450 CYP2D6/genética , Farmacogenética/normas , Analgésicos Opioides/efeitos adversos , Cálculos da Dosagem de Medicamento , Testes Genéticos/normas , Humanos , Fenótipo , Polimorfismo Genético
15.
Clin Pharmacol Ther ; 88(5): 643-51, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20881950

RESUMO

The pharmacokinetics of dextromethorphan (DM) is markedly influenced by cytochrome P450 2D6 (CYP2D6) enzyme polymorphisms. The aim of this study was to quantify the effects of the CYP2D6*1, *2, and *41 variants on DM metabolism in vivo and to identify other sources of pharmacokinetic variability. Concentrations of DM and dextrorphan (DO) in plasma and urine were evaluated in 36 healthy Caucasian men. These volunteers participated in three clinical studies and received a single oral dose of 30 mg DM-HBr. Data were modeled simultaneously using the population pharmacokinetics NONMEM software. A five-compartment model adequately described the data. The activity levels of the alleles assessed differed significantly. The clearance attributable to an individual CYP2D6*1 copy was 2.5-fold higher as compared with CYP2D6*2 (5,010 vs. 2,020 l/h), whereas the metabolic activity of CYP2D6*41 was very low (85 l/h). Urinary pH was confirmed as a significant covariate for DM renal clearance. These results refine genotype-based predictions of pharmacokinetics for DM and presumably for other CYP2D6 substrates as well.


Assuntos
Antitussígenos/farmacocinética , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Dextrometorfano/farmacocinética , Dextrorfano/farmacocinética , Modelos Biológicos , Polimorfismo Genético , Administração Oral , Adulto , Antitussígenos/administração & dosagem , Antitussígenos/sangue , Antitussígenos/urina , Biotransformação , Ensaios Clínicos como Assunto , Dextrometorfano/administração & dosagem , Dextrometorfano/sangue , Dextrometorfano/urina , Dextrorfano/sangue , Dextrorfano/urina , Frequência do Gene , Genótipo , Humanos , Concentração de Íons de Hidrogênio , Masculino , Pessoa de Meia-Idade , Fenótipo , População Branca/genética , Adulto Jovem
16.
Clin Pharmacol Ther ; 85(1): 31-5, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18719619

RESUMO

A large number of women receive codeine for obstetric pain while breastfeeding. Following a case of fatal opioid poisoning in a breastfed neonate whose codeine prescribed mother was a CYP2D6 ultrarapid metabolizer (UM), we examined characteristics of mothers and infants with or without signs of central nervous system (CNS) depression following codeine exposure while breastfeeding in a case-control study. Mothers of symptomatic infants (n = 17) consumed a mean 59% higher codeine dose than mothers of asymptomatic infants (n = 55) (1.62 (0.79) mg/kg/day vs. 1.02 (0.54) mg/kg/day; P = 0.004). There was 71% concordance between maternal and neonatal CNS depression. Two mothers whose infants exhibited severe neonatal toxicity were CYP2D6 UMs and of the UGT2B7*2/*2 genotype. There may be a dose-response relationship between maternal codeine use and neonatal toxicity, and strong concordance between maternal-infant CNS depressive symptoms. Breastfed infants of mothers who are CYP2D6 UMs combined with the UGT2B7*2/*2 are at increased risk of potentially life-threatening CNS depression.


Assuntos
Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/metabolismo , Aleitamento Materno/efeitos adversos , Codeína/efeitos adversos , Codeína/metabolismo , Citocromo P-450 CYP2D6/genética , Leite Humano/química , Transtornos Relacionados ao Uso de Opioides/etiologia , Transtornos Relacionados ao Uso de Opioides/genética , Adulto , Analgésicos Opioides/uso terapêutico , Apneia/induzido quimicamente , Estudos de Casos e Controles , Codeína/uso terapêutico , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Transtornos Relacionados ao Uso de Opioides/fisiopatologia , Dor/tratamento farmacológico , Farmacogenética
18.
Clin Pharmacol Ther ; 83(2): 234-42, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17971818

RESUMO

Inferring CYP2D6 phenotype from genotype is increasingly challenging, considering the growing number of alleles and their range of activity. This complexity poses a challenge in translational research where genotyping is being considered as a tool to personalize drug therapy. To simplify genotype interpretation and improve phenotype prediction, we evaluated the utility of an "activity score" (AS) system. Over 25 CYP2D6 allelic variants were genotyped in 672 subjects of primarily Caucasian and African-American heritage. The ability of genotype and AS to accurately predict phenotype using the CYP2D6 probe substrate dextromethorphan was evaluated using linear regression and clustering methods. Phenotype prediction, given as a probability for each AS group, was most accurate if ethnicity was considered; among subjects with genotypes containing a CYP2D6*2 allele, CYP2D6 activity was significantly slower in African Americans compared to Caucasians. The AS tool warrants further prospective evaluation for CYP2D6 substrates and in additional ethnic populations.


Assuntos
População Negra/genética , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Modelos Genéticos , Farmacogenética , Polimorfismo Genético , População Branca/genética , Adolescente , Adulto , Criança , Pré-Escolar , Análise por Conglomerados , Estudos de Coortes , Dextrometorfano/metabolismo , Dextrometorfano/urina , Frequência do Gene , Genótipo , Humanos , Lactente , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Fenótipo , Reprodutibilidade dos Testes , Especificidade por Substrato , Estados Unidos
19.
Drug Metab Dispos ; 35(7): 1064-70, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17403913

RESUMO

Arylamine N-acetyltransferases (NAT) catalyze the biotransformation of many important arylamine drugs and procarcinogens. NAT can either detoxify or activate procarcinogens, complicating the manner in which these enzymes may participate in enhancing or preventing toxic responses to particular agents. Mice possess three NAT isoenzymes: Nat1, Nat2, and Nat3. Whereas Nat1 and Nat2 can efficiently acetylate many arylamines, few substrates appear to be appreciably metabolized by Nat3. We generated a Nat3 knockout mouse strain and used it along with our double Nat1/2(-/-) knockout strain to further investigate the functional role of Nat3. Nat3(-/-) mice showed normal viability and reproductive capacity. Nat3 expression was very low in wild-type animals and completely undetectable in Nat3(-/-) mice. In contrast, greatly elevated expression of Nat3 transcript was observed in Nat1/2(-/-) mice. We used a transcribed marker polymorphism approach to establish that the increased expression of Nat3 in Nat1/2(-/-) mice is a positional artifact of insertion of the phosphoglycerate kinase-neomycin resistance cassette in place of the Nat1/Nat2 gene region and upstream of the intact Nat3 gene, rather than a biological compensatory mechanism. Despite the increase in Nat3 transcript, the N-acetylation of p-aminosalicylate, sulfamethazine, 2-aminofluorene, and 4-aminobiphenyl was undetectable either in vivo or in vitro in Nat1/2(-/-) animals. In parallel, no difference was observed in the in vivo clearance or in vitro metabolism of any of these substrates between wild-type and Nat3(-/-) mice. Thus, Nat3 is unlikely to play a significant role in the N-acetylation of arylamines either in wild-type mice or in mice lacking Nat1 and Nat2 activities.


Assuntos
Artefatos , Arilamina N-Acetiltransferase/metabolismo , Regulação Enzimológica da Expressão Gênica , Isoenzimas/metabolismo , Acetilação , Compostos de Aminobifenil/metabolismo , Ácido Aminossalicílico/metabolismo , Animais , Arilamina N-Acetiltransferase/deficiência , Arilamina N-Acetiltransferase/genética , Feminino , Fluorenos/metabolismo , Isoenzimas/deficiência , Isoenzimas/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Mensageiro/metabolismo , Fatores Sexuais , Especificidade por Substrato , Sulfametazina/metabolismo
20.
Clin Pharmacol Ther ; 81(6): 817-20, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17392730

RESUMO

A 5-year-old African-American girl presented with a CYP2D6*4xN/*10 genotype that was discordant with her poor metabolizer phenotype determined with the probe drug dextromethorphan. Both phenotype and genotype were confirmed in repeat assessments, suggesting that the CYP2D6*10 allele carried a novel debilitating sequence variation(s). The rationale for this study was to resolve the discordance and to describe the novel non-functional allelic variant of CYP2D6 and its frequency in populations of different ethnic backgrounds.


Assuntos
Citocromo P-450 CYP2D6/genética , Negro ou Afro-Americano , Pré-Escolar , Citocromo P-450 CYP2D6/metabolismo , Dextrometorfano/farmacocinética , Feminino , Frequência do Gene , Genótipo , Humanos , Dados de Sequência Molecular , Fenótipo
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