RESUMO
AIMS: The aims of this study were to describe the pharmacokinetics of tacrolimus immediately after kidney transplantation, and to develop a clinical tool for selecting the best starting dose for each patient. METHODS: Data on tacrolimus exposure were collected for the first 3 months following renal transplantation. A population pharmacokinetic analysis was conducted using nonlinear mixed-effects modelling. Demographic, clinical and genetic parameters were evaluated as covariates. RESULTS: A total of 4527 tacrolimus blood samples collected from 337 kidney transplant recipients were available. Data were best described using a two-compartment model. The mean absorption rate was 3.6 h-1 , clearance was 23.0 l h-1 (39% interindividual variability, IIV), central volume of distribution was 692 l (49% IIV) and the peripheral volume of distribution 5340 l (53% IIV). Interoccasion variability was added to clearance (14%). Higher body surface area (BSA), lower serum creatinine, younger age, higher albumin and lower haematocrit levels were identified as covariates enhancing tacrolimus clearance. Cytochrome P450 (CYP) 3A5 expressers had a significantly higher tacrolimus clearance (160%), whereas CYP3A4*22 carriers had a significantly lower clearance (80%). From these significant covariates, age, BSA, CYP3A4 and CYP3A5 genotype were incorporated in a second model to individualize the tacrolimus starting dose: [Formula: see text] Both models were successfully internally and externally validated. A clinical trial was simulated to demonstrate the added value of the starting dose model. CONCLUSIONS: For a good prediction of tacrolimus pharmacokinetics, age, BSA, CYP3A4 and CYP3A5 genotype are important covariates. These covariates explained 30% of the variability in CL/F. The model proved effective in calculating the optimal tacrolimus dose based on these parameters and can be used to individualize the tacrolimus dose in the early period after transplantation.
Assuntos
Rejeição de Enxerto/prevenção & controle , Imunossupressores/farmacocinética , Transplante de Rim/efeitos adversos , Modelos Biológicos , Tacrolimo/farmacocinética , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Variação Biológica da População/fisiologia , Simulação por Computador , Citocromo P-450 CYP3A/genética , Relação Dose-Resposta a Droga , Feminino , Rejeição de Enxerto/imunologia , Humanos , Imunossupressores/administração & dosagem , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Tacrolimo/administração & dosagem , Transplantados , Adulto JovemRESUMO
Patients expressing the cytochrome P450 (CYP) 3A5 gene require a higher tacrolimus dose to achieve therapeutic exposure compared with nonexpressers. This randomized-controlled study investigated whether adaptation of the tacrolimus starting dose according to CYP3A5 genotype increases the proportion of kidney transplant recipients being within the target tacrolimus predose concentration range (10-15 ng/mL) at first steady-state. Two hundred forty living-donor, renal transplant recipients were assigned to either receive a standard, body-weight-based or a CYP3A5 genotype-based tacrolimus starting dose. At day 3, no difference in the proportion of patients having a tacrolimus exposure within the target range was observed between the standard-dose and genotype-based groups: 37.4% versus 35.6%, respectively; p = 0.79. The proportion of patients with a subtherapeutic (i.e. <10 ng/mL) or a supratherapeutic (i.e. >15 ng/mL) Tac predose concentration in the two groups was also not significantly different. The incidence of acute rejection was comparable between both groups (p = 0.82). Pharmacogenetic adaptation of the tacrolimus starting dose does not increase the number of patients having therapeutic tacrolimus exposure early after transplantation and does not lead to improved clinical outcome in a low immunological risk population.
Assuntos
Peso Corporal , Citocromo P-450 CYP3A/genética , Rejeição de Enxerto/genética , Falência Renal Crônica/cirurgia , Transplante de Rim , Doadores Vivos , Tacrolimo/uso terapêutico , Adulto , Idoso , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Genótipo , Taxa de Filtração Glomerular , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/epidemiologia , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Imunossupressores/uso terapêutico , Falência Renal Crônica/genética , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Polimorfismo de Nucleotídeo Único , Complicações Pós-Operatórias , Prevalência , Prognóstico , Estudos Prospectivos , Fatores de Risco , Adulto JovemRESUMO
Docetaxel is used for treatment of several solid malignancies. In this study, we aimed for predicting docetaxel clearance and docetaxel-induced neutropenia by developing several genetic models. Therefore, pharmacokinetic data and absolute neutrophil counts (ANCs) of 213 docetaxel-treated cancer patients were collected. Next, patients were genotyped for 1936 single nucleotide polymorphisms (SNPs) in 225 genes using the drug-metabolizing enzymes and transporters platform and thereafter split into two cohorts. The combination of SNPs that best predicted severe neutropenia or low clearance was selected in one cohort and validated in the other. Patients with severe neutropenia had lower docetaxel clearance than patients with ANCs in the normal range (P=0.01). Severe neutropenia was predicted with 70% sensitivity. True low clearance (1 s.d.Assuntos
Antineoplásicos/efeitos adversos
, Antineoplásicos/farmacocinética
, Neutropenia/genética
, Variantes Farmacogenômicos
, Polimorfismo de Nucleotídeo Único
, Taxoides/efeitos adversos
, Taxoides/farmacocinética
, Adolescente
, Adulto
, Idoso
, Idoso de 80 Anos ou mais
, Antineoplásicos/administração & dosagem
, Bases de Dados Genéticas
, Docetaxel
, Feminino
, Predisposição Genética para Doença
, Humanos
, Inativação Metabólica/genética
, Masculino
, Proteínas de Membrana Transportadoras/genética
, Proteínas de Membrana Transportadoras/metabolismo
, Taxa de Depuração Metabólica/genética
, Pessoa de Meia-Idade
, Modelos Genéticos
, Neutropenia/induzido quimicamente
, Farmacogenética
, Fenótipo
, Fatores de Risco
, Índice de Gravidade de Doença
, Taxoides/administração & dosagem
, Adulto Jovem
RESUMO
The overall goal of this study was to provide evidence for the clinical validity of nine genetic variants in five genes previously associated with irinotecan neutropenia and pharmacokinetics. Variants associated with absolute neutrophil count (ANC) nadir and/or irinotecan pharmacokinetics in a discovery cohort of cancer patients were genotyped in an independent replication cohort of 108 cancer patients. Patients received single-agent irinotecan every 3 weeks. For ANC nadir, we replicated UGT1A1*28, UGT1A1*93 and SLCO1B1*1b in univariate analyses. For irinotecan area under the concentration-time curve (AUC0-24), we replicated ABCC2 -24C>T; however, ABCC2 -24C>T only predicted a small fraction of the variance. For SN-38 AUC0-24 and the glucuronidation ratio, we replicated UGT1A1*28 and UGT1A1*93. In addition to UGT1A1*28, this study independently validated UGT1A1*93 and SLCO1B1*1b as new predictors of irinotecan neutropenia. Further demonstration of their clinical utility will optimize irinotecan therapy in cancer patients.
Assuntos
Antineoplásicos/efeitos adversos , Camptotecina/análogos & derivados , Marcadores Genéticos , Neoplasias/tratamento farmacológico , Neutropenia/induzido quimicamente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacocinética , Camptotecina/efeitos adversos , Camptotecina/farmacocinética , Estudos de Coortes , Feminino , Genótipo , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Proteína 2 Associada à Farmacorresistência Múltipla , Neoplasias/genética , Neutropenia/genéticaRESUMO
Cyclosporine is used extensively in kidney transplantation and is a substrate for cytochrome P450 enzymes. The role of cytochrome p450 polymorphisms in kidney transplant outcome has not yet been fully elucidated. We investigate the clinical impact of single nucleotide polymorphisms in CYP3A4, CYP3A5, PPARα, and POR*28 in 255 kidney transplant recipients. We examine for any association with graft survival, time to first cancer, and delayed graft function, and also measure cyclosporine levels at days 3, 10, and months 1, 3, 6, and 12 after transplantation. The CYP3A4*22 allele is significant associated with the development of cancer post-kidney transplantation (HR 0.20, 95% CI 0.07-0.57, p = 0.003). It is not significantly associated with graft survival. No other SNP's were associated with graft survival time to first cancer, or delayed graft function. There was a non-significant trend of lower cyclosporine dose requirement in CYP3A4*22 carriers. Independent replication of our findings is now warranted to confirm or reject the role of CYP3A variants in cancer development following kidney transplantation.
Assuntos
Citocromo P-450 CYP3A/genética , Sobrevivência de Enxerto/genética , Transplante de Rim , Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Complicações Pós-Operatórias/genética , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Estrogen catabolism is a major function of CYP2C19. The effect of CYP2C19 polymorphisms on tamoxifen sensitivity may therefore not only be mediated by a variation in tamoxifen metabolite levels but also by an effect on breast cancer risk and molecular subtype due to variation in lifelong exposure to estrogens. We determined the association between these polymorphisms and tamoxifen sensitivity in the context of a randomized trial, which allows for the discernment of prognosis from prediction. We isolated primary tumor DNA from 535 estrogen receptor-positive, stages I-III, postmenopausal breast cancer patients who had been randomized to tamoxifen (1-3 years) or no adjuvant therapy. Recurrence-free interval improvement with tamoxifen versus control was assessed according to the presence or absence of CYP2C19 2 and CYP2C19 17. Hazard ratios and interaction terms were calculated using multivariate Cox proportional hazard models, stratified for nodal status. Tamoxifen benefit was not significantly affected by CYP2C19 17. Patients with at least one CYP2C19 2 allele derived significantly more benefit from tamoxifen (HR 0.26; p = 0.001) than patients without a CYP2C19 2 allele (HR 0.68; p = 0.18) (p for interaction 0.04). In control patients, CYP2C19 2 was an adverse prognostic factor. In conclusion, breast cancer patients carrying at least one CYP2C19 2 allele have an adverse prognosis in the absence of adjuvant systemic treatment, which can be substantially improved by adjuvant tamoxifen treatment.
Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Polimorfismo Genético , Tamoxifeno/uso terapêutico , Idoso , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/metabolismo , Quimioterapia Adjuvante , Citocromo P-450 CYP2C19 , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Pós-Menopausa/genética , Valor Preditivo dos Testes , Prognóstico , Resultado do TratamentoRESUMO
The clinical importance of CYP2D6 genotype as predictor of tamoxifen efficacy is still unclear. Recent genotyping studies on CYP2D6 using DNA derived from tumor blocks have been criticized because loss of heterozygosity (LOH) in tumors may lead to false genotype assignment. Postmenopausal early breast cancer patients who were randomized to receive tamoxifen, followed by exemestane in a large randomized controlled trial were genotyped for five CYP2D6 alleles. CYP2D6 genotypes and phenotypes were related to disease-free survival during tamoxifen use (DFS-t) in 731 patients. By analyzing microsatellites flanking the CYP2D6 gene, patients whose genotyping results were potentially affected by LOH were excluded. In addition, exploratory analyses on 24 genetic variants of other metabolic enzymes and the estrogen receptor were performed. For the CYP2D6 analysis, only 2.3 % of the samples were excluded, because influence of LOH could not be ruled out. No association was found between the CYP2D6 genotype or predicted phenotype and DFS-t (poor vs. extensive metabolizers: unadjusted hazard ratio 1.33, 95 % CI 0.52-3.43; P = 0.55). DFS-t was associated with UGT2B15*2 (Vt/Vt + Wt/Vt vs. Wt/Wt: adjusted hazard ratio 0.47, 95 % CI 0.25-0.89; P = 0.019) and the estrogen receptor-1 polymorphism ESR1 PvuII (gene-dose effect: adjusted hazard ratio 1.63, 95 % CI 1.04-2.54; P = 0.033). In postmenopausal early breast cancer patients treated with adjuvant tamoxifen followed by exemestane neither CYP2D6 genotype nor phenotype did affect DFS-t. This is in accordance with two recent studies in the BIG1-98 and ATAC trials. Our study is the first CYP2D6 association study using DNA from paraffin-embedded tumor tissue in which potentially false interpretation of genotyping results because of LOH was excluded. Polymorphisms in the estrogen receptor-1 and UGT2B15 may be associated with tamoxifen efficacy, but these findings need replication.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Citocromo P-450 CYP2D6/genética , Tamoxifeno/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Receptor alfa de Estrogênio/genética , Feminino , Genótipo , Humanos , Perda de Heterozigosidade/genética , Pessoa de Meia-Idade , Polimorfismo Genético , Fatores de RiscoRESUMO
Several statins are substrates for the multidrug resistance-associated protein 2 transporter, encoded by the ABCC2 gene. We analyzed in the Rotterdam Study whether the common polymorphisms -24C>T, 1249G>A and 3972C>T in the ABCC2 gene were associated with a dose decrease or switch to another cholesterol-lowering drug in simvastatin and atorvastatin users. These events could indicate an adverse effect or a too strong reduction in cholesterol level. We identified 1014 simvastatin and atorvastatin users during the period 1 January 1991 to 1 January 2010. Associations between genetic variation and the risk of these events were analyzed using Cox proportional hazards modelling. The ABCC2 -24C>T genotype (HR 1.32 95% CI 1.04-1.69) and the H12 haplotype versus the H2 haplotype (HR 1.49; 95% CI 1.06-2.09) were associated with these events in simvastatin users. A similar but not significant association was found in atorvastatin users. To conclude, genetic variation in the ABCC2 gene is associated with these events in simvastatin users.
Assuntos
Relação Dose-Resposta a Droga , Ácidos Heptanoicos/administração & dosagem , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Pirróis/administração & dosagem , Sinvastatina/administração & dosagem , Idoso , Anticolesterolemiantes/administração & dosagem , Atorvastatina , Colesterol/genética , Colesterol/metabolismo , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Feminino , Estudos de Associação Genética , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 2 Associada à Farmacorresistência Múltipla , Polimorfismo de Nucleotídeo Único , Modelos de Riscos ProporcionaisRESUMO
BACKGROUND: The main cause for fluoropyrimidine-related toxicity is deficiency of the metabolizing enzyme dihydropyrimidine dehydrogenase (DPD). In 2020, the European Medicines Agency (EMA) recommended two methods for pre-treatment DPD deficiency testing in clinical practice: phenotyping using endogenous uracil concentration or genotyping for DPYD risk variant alleles. This study assessed the DPD testing implementation status in Europe before (2019) and after (2021) the release of the EMA recommendations. METHODS: The survey was conducted from 16 March 2022 to 31 July 2022. An electronic form with seven closed and three open questions was e-mailed to 251 professionals with DPD testing expertise of 34 European countries. A descriptive analysis was conducted. RESULTS: We received 79 responses (31%) from 23 countries. Following publication of the EMA recommendations, 87% and 75% of the countries reported an increase in the amount of genotype and phenotype testing, respectively. Implementation of novel local guidelines was reported by 21 responders (27%). Countries reporting reimbursement of both tests increased in 2021, and only four (18%) countries reported no coverage for any testing type. In 2019, major implementation drivers were 'retrospective assessment of fluoropyrimidine-related toxicity' (39%), and in 2021, testing was driven by 'publication of guidelines' (40%). Although the major hurdles remained the same after EMA recommendations-'lack of reimbursement' (26%; 2019 versus 15%; 2021) and 'lack of recognizing the clinical relevance by medical oncologists' (25%; 2019 versus 8%; 2021)-the percentage of specialists citing these decreased. Following EMA recommendations, 25% of responders reported no hurdles at all in the adoption of the new testing practice in the clinics. CONCLUSIONS: The EMA recommendations have supported the implementation of DPD deficiency testing in Europe. Key factors for successful implementation were test reimbursement and clear clinical guidelines. Further efforts to improve the oncologists' awareness of the clinical relevance of DPD testing in clinical practice are needed.
Assuntos
Deficiência da Di-Hidropirimidina Desidrogenase , Humanos , Deficiência da Di-Hidropirimidina Desidrogenase/diagnóstico , Deficiência da Di-Hidropirimidina Desidrogenase/genética , Deficiência da Di-Hidropirimidina Desidrogenase/tratamento farmacológico , Fluoruracila/uso terapêutico , Antimetabólitos Antineoplásicos/uso terapêutico , Estudos Retrospectivos , Di-Hidrouracila Desidrogenase (NADP)/genética , Europa (Continente)RESUMO
The goals of the Association for Molecular Pathology Clinical Practice Committee's Pharmacogenomics (PGx) Working Group are to define the key attributes of pharmacogenetic alleles recommended for clinical testing and a minimum set of variants that should be included in clinical PGx genotyping assays. This article provides recommendations for a minimum panel of variant alleles (Tier 1) and an extended panel of variant alleles (Tier 2) that will aid clinical laboratories when designing assays for PGx testing. The Association for Molecular Pathology PGx Working Group considered the functional impact of the variant alleles, allele frequencies in multiethnic populations, the availability of reference materials, as well as other technical considerations for PGx testing when developing these recommendations. The ultimate goal of this Working Group is to promote standardization of PGx gene/allele testing across clinical laboratories. This article focuses on clinical TPMT and NUDT15 PGx testing, which may be applied to all thiopurine S-methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15)-related medications. These recommendations are not to be interpreted as prescriptive, but to provide a reference guide.
Assuntos
Patologia Molecular , Farmacogenética , Pirofosfatases/genética , Consenso , Genótipo , Humanos , Bases de Conhecimento , Metiltransferases , Patologistas , FarmacêuticosRESUMO
Effective pharmacologic treatments for psychiatric disorders are available, but their effect is limited due to patients' genetic heterogeneity and low compliance-related to frequent adverse events. Only one third of patients respond to treatment and experience remission. Pharmacogenetics is a relatively young field which focusses on genetic analyses in the context of the metabolism and outcome of drug treatment. These genetic factors can, among other things, lead to differences in the activity of enzymes that metabolize drugs. Recently, a clinical guideline was authorized by the Dutch Clinical Psychiatric Association (NVvP) on the clinical use of pharmacogenetics in psychiatry. The main goal was to provide guidance, based on current evidence, on how to best use genotyping in clinical psychiatric practice. A systematic literature search was performed, and available publications were assessed using the GRADE methodology. General recommendations for psychiatric clinical practice were provided, and specific recommendations per medication were made available. This clinical guideline for caregivers prescribing psychotropic drugs is the product of a broad collaboration of professionals from different disciplines, making use of the information available at the Dutch Pharmacogenetics Working Group (DPWG) and the Clinical Pharmacogenetics Implementation Consortium (CPIC) so far. We summarize the relevant literature and all recommendations in this article. General recommendations are provided and also detailed recommendations per medication. In summary we advise to consider genotyping, when there are side effects or inefficacy for CYP2C19 and CYP2D6. When genotype information is available use this to select the right drug in the right dose for the right patient.
RESUMO
The analysis of circulating cell free DNA is an important tool for the analysis of tumor resistance, tumor heterogeneity, detection of minimal residual disease and detection of allograft rejection in kidney or heart transplant patients. The proper use of this technique is important, and starts with considering pre-analytic aspects. The current paper addresses some important technical considerations to ensure the proper and harmonized use of cfDNA techniques.
Assuntos
Ácidos Nucleicos Livres , DNA Tumoral Circulante , Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , Testes Diagnósticos de Rotina , Humanos , Neoplasia ResidualRESUMO
The goals of the Association for Molecular Pathology Clinical Practice Committee's Pharmacogenomics (PGx) Working Group are to define the key attributes of pharmacogenetic alleles recommended for clinical testing, and to determine a minimal set of variants that should be included in clinical PGx genotyping assays. This document series provides recommendations on a minimal panel of variant alleles (Tier 1) and an extended panel of variant alleles (Tier 2) that will aid clinical laboratories in designing assays for PGx testing. When developing these recommendations, the Association for Molecular Pathology PGx Working Group considered the functional impact of the variant alleles, allele frequencies in multiethnic populations, the availability of reference materials, as well as other technical considerations with regard to PGx testing. The ultimate goal of this Working Group is to promote standardization of PGx gene/allele testing across clinical laboratories. This document is focused on clinical CYP2D6 PGx testing that may be applied to all cytochrome P450 2D6-metabolized medications. These recommendations are not meant to be interpreted as prescriptive but to provide a reference guide for clinical laboratories that may be either implementing PGx testing or reviewing and updating their existing platform.
Assuntos
Alelos , Consenso , Citocromo P-450 CYP2D6/genética , Genótipo , Técnicas de Genotipagem/métodos , Testes Farmacogenômicos/normas , Medicina de Precisão/normas , Frequência do Gene , Humanos , Laboratórios Clínicos , Países Baixos , Patologistas/psicologia , Farmacêuticos/psicologia , Sociedades Médicas , Estados UnidosRESUMO
BACKGROUND: Cytochrome P450 2D6 (CYP2D6) has a crucial role in the metabolic conversion of tamoxifen into the active metabolite endoxifen. In this cohort study, the effect of CYP2D6-predicted phenotype, defined as the combined effect of CYP2D6 genetic variation and concomitant use of CYP2D6-inhibiting medication, on time to breast cancer progression (TTP) and overall survival (OS) in women who use tamoxifen for metastatic breast cancer (MBC) was examined. METHODS: We selected patients treated with tamoxifen (40 mg per day) for hormone receptor-positive MBC from whom a blood sample for pharmacogenetic analysis (CYP2D6*3, *4, *5, *6, *10 and *41) was available. Patient charts (n=102) were reviewed to assess TTP and OS, and to determine whether CYP2D6 inhibitors were prescribed during tamoxifen treatment. RESULTS: OS was significantly shorter in patients with a poor CYP2D6 metaboliser phenotype, compared with extensive metabolisers (HR=2.09; P=0.034; 95% CI: 1.06-4.12). Co-administration of CYP2D6 inhibitors alone was also associated with a worse OS (HR=3.55; P=0.002; 95% CI: 1.59-7.96) and TTP (HR=2.97; P=0.008; 95% CI: 1.33-6.67) compared with patients without CYP2D6 inhibitors. CONCLUSION: CYP2D6 phenotype is an important predictor of treatment outcome in women who are receiving tamoxifen for MBC. Co-administration of CYP2D6 inhibitors worsens treatment outcome of tamoxifen and should therefore be handled with care.
Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Citocromo P-450 CYP2D6/metabolismo , Metástase Neoplásica/tratamento farmacológico , Tamoxifeno/uso terapêutico , Adulto , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Estudos de Coortes , Citocromo P-450 CYP2D6/genética , Inibidores do Citocromo P-450 CYP2D6 , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Farmacogenética , Fenótipo , Resultado do TratamentoRESUMO
CYP2C19 converts the tricyclic antidepressant imipramine to its active metabolite desipramine, which is subsequently inactivated by CYP2D6. The novel CYP2C19*17 allele causes ultrarapid metabolism of CYP2C19 substrates. We genotyped 178 depressed patients on imipramine for CYP2C19*17, and measured steady-state imipramine and desipramine plasma concentrations. Mean dose-corrected imipramine plasma concentration was significantly dependent on CYP2C19 genotype (Kruskal-Wallis test, P=0.01), with circa 30% lower levels in CYP2C19*17/*17 individuals compared with CYP2C19*1/*1 (wild-type) patients. The mean dose-corrected imipramine+desipramine plasma concentrations and imipramine/desipramine ratios were not significantly different between genotype subgroups (Kruskal-Wallis tests, P>or=0.12). In a multivariate analysis, we found a significant, but limited effect (P=0.035, eta(2)=0.031) of the CYP2C19*17 genotype on imipramine+desipramine concentrations. Although the CYP2C19*17 allele is associated with a significantly increased metabolism of imipramine, CYP2C19*17 genotyping will, in our view, not importantly contribute to dose management of patients on imipramine therapy guided by imipramine+desipramine plasma concentrations.
Assuntos
Antidepressivos Tricíclicos/sangue , Hidrocarboneto de Aril Hidroxilases/genética , Depressão/tratamento farmacológico , Imipramina/sangue , Adulto , Antidepressivos Tricíclicos/uso terapêutico , Citocromo P-450 CYP2C19 , Depressão/genética , Desipramina/sangue , Genótipo , Humanos , Imipramina/uso terapêutico , Pessoa de Meia-Idade , Análise MultivariadaAssuntos
Alanina Transaminase/metabolismo , Azatioprina/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Inibidores da Bomba de Prótons/efeitos adversos , gama-Glutamiltransferase/metabolismo , 2-Piridinilmetilsulfinilbenzimidazóis/efeitos adversos , Idoso , Dermatite Atópica/tratamento farmacológico , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Dermatoses do Pé/tratamento farmacológico , Dermatoses da Mão/tratamento farmacológico , Humanos , Pessoa de Meia-Idade , Omeprazol/efeitos adversos , PantoprazolRESUMO
With the exception of a few medical specialties, the implementation of pharmacogenetic tests in daily practice has thus far been limited. The Royal Dutch Pharmacists Association (KNMP) has developed pharmacogenetics-based therapeutic doserecommendations for 80 medicinal product combinations on the basis of a systematic literature review. Genotyping of patients can take place on a reactive or pre-emptive basis; the advantage of pre-emptive genotyping is that it provides genetic information the moment a medicinal product is prescribed. Clinical decision support software is crucial to implement pharmacogenetics into daily practice.
Assuntos
Sistemas de Apoio a Decisões Clínicas , Prescrições de Medicamentos/normas , Farmacogenética/normas , Testes Farmacogenômicos/normas , Cálculos da Dosagem de Medicamento , Técnicas de Genotipagem , Humanos , Países Baixos , Farmacêuticos/organização & administração , Farmacogenética/métodos , Testes Farmacogenômicos/métodos , Revisões Sistemáticas como AssuntoRESUMO
The organic cation transporter 1, encoded by the SLC22A1 gene, is responsible for the uptake of the anti-hyperglycaemic drug, metformin, in the hepatocyte. We assessed whether a genetic variation in the SLC22A1 gene is associated with the glucose-lowering effect of metformin. Incident metformin users in the Rotterdam Study, whose HbA1c measurements were available, were identified. Associations between 11 tagging single nucleotide polymorphisms in the SLC22A1 gene and change in the HbA1c level were analyzed. A total of 102 incident metformin users were included in this study sample. Except for the rs622342 A>C polymorphism, no significant differences in metformin response were observed. For each minor C allele at rs622342, the reduction in HbA1c levels was 0.28% less (95% CI 0.09-0.47, P=0.005). After Bonferroni correction, the P-value was 0.050. To conclude, genetic variation at rs622342 in the SLC22A1 gene was associated with the glucose-lowering effect of metformin in patients with diabetes mellitus.