Assuntos
Antipsicóticos , Risperidona , Humanos , Risperidona/efeitos adversos , Risperidona/uso terapêutico , Adolescente , Criança , Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Masculino , Feminino , Resultado do TratamentoRESUMO
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
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
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
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
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
INTRODUCTION: Tacrolimus (Tac) is effective in preventing acute rejection but has considerable toxicity and inter-individual variability in pharmacokinetics and pharmacodynamics. Part of this is explained by polymorphisms in genes encoding Tac-metabolizing enzymes and transporters. A better understanding of Tac pharmacokinetics and pharmacodynamics may help to minimize different outcomes amongst transplant recipients by personalizing immunosuppression. AREAS COVERED: The pharmacogenetic contribution of Tac metabolism will be examined, with a focus on recent discoveries, new developments and ethnic considerations. EXPERT OPINION: The strongest and most consistent association in pharmacogenetics is between the CYP3A5 genotype and Tac dose requirement, with CYP3A5 expressers having a ~ 40-50% higher dose requirement compared to non-expressers. Two recent randomized-controlled clinical trials using CYP3A5 genotype, however, did not show a decrease in acute rejections nor reduced toxicity. CYP3A4*22, CYP3A4*26, and POR*28 are also associated with Tac dose requirements and may be included to provide the expected improvement of Tac therapy. Studies focusing on the intracellular drug concentrations and on calcineurin inhibitor-induced nephrotoxicity also seem promising. For all studies, however, the ethnic prevalence of genotypes should be taken into account, as this may significantly impact the effect of pre-emptive genotyping.
Assuntos
Imunossupressores/administração & dosagem , Transplante de Rim/métodos , Tacrolimo/administração & dosagem , Citocromo P-450 CYP3A/genética , Etnicidade , Genótipo , Rejeição de Enxerto/prevenção & controle , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/farmacocinética , Farmacogenética/métodos , Polimorfismo Genético , Medicina de Precisão/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Tacrolimo/efeitos adversos , Tacrolimo/farmacocinéticaRESUMO
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
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
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 JovemAssuntos
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
BACKGROUND: This study was initiated to explore the impact of organic cation transporter 1 (OCT1) and multidrug and toxin extrusion transporter 1 (MATE1) genetic polymorphisms on toxicity, and clinical activity of metformin in patients with castration-resistant prostate cancer (CRPC). METHODS: The SAKK 08/09 trial included 44 patients with CRPC to receive single-agent metformin 1000 mg two times a day until disease progression or unwanted toxicity. Drug pathway-associated gene polymorphisms of OCT1 (rs622342) and MATE1 (rs2289669) were assessed. The primary objective of this study was to define the relationship between mutations in OCT1, MATE1 and progression-free survival (PFS) at 12 weeks absolute PFS and PSA response in consenting patients of SAKK 08/09. The secondary objective of this study was to analyze the association between mutations in OCT1, MATE1, metformin-related toxicity, PSA response at 12 weeks and overall survival. RESULTS: Thirty-six patients were evaluable for pharmacogenetic analysis. Homozygous carriers of the polymorphic OCT1 C-allele had no metformin-related toxicity as compared with 41.9% for any metformin-related toxicity in carriers of at least one wild-type A-allele (P=0.07). Disease progression according to RECIST (Response Evaluation Criteria In Solid Tumors) was significantly more frequent in homozygous carriers of the polymorphic OCT1 C-allele (80%) as compared with carriers of at least one wild-type A-allele (28.6%) (P=0.002). Disease progression according to RECIST was also more frequent in carriers of at least one polymorphic MATE1 A-allele (44%) as compared with homozygous carriers of the wild-type G-allele (12.5%) (P=0.07). OCT1 and MATE1 were not associated with PFS. CONCLUSIONS: The polymorphic OCT1 C-allele has been shown to be associated with less metformin-related toxicity and a higher risk of tumor progression in patients with CRPC receiving metformin as an anticancer treatment. Polymorphisms in metformin drug transporters are attractive molecular markers to serve as potential predictors of efficacy in future clinical studies.
Assuntos
Metformina/efeitos adversos , Proteínas de Transporte de Cátions Orgânicos/genética , Transportador 1 de Cátions Orgânicos/genética , Neoplasias de Próstata Resistentes à Castração/genética , Idoso , Idoso de 80 Anos ou mais , Alelos , Intervalo Livre de Doença , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológicoRESUMO
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
Interpatient variability in the pharmacokinetics (PK) of sunitinib is high. Single nucleotide polymorphisms (SNPs) in PK candidate genes have been associated with the efficacy and toxicity of sunitinib, but whether these SNPs truly affect the PK of sunitinib remains to be elucidated. This multicenter study involving 114 patients investigated whether these SNPs and haplotypes in genes encoding metabolizing enzymes or efflux transporters are associated with the clearance of sunitinib and its active metabolite SU12662. SNPs were tested as covariates in a population PK model. From univariate analysis, we found that the SNPs in CYP3A4, CYP3A5, and ABCB1 were associated with the clearance of both sunitinib and SU12662. In multivariate analysis, CYP3A4*22 was found to be eliminated last with an effect size of -22.5% on clearance. Observed effect sizes are below the interindividual variability in clearance and are therefore too limited to directly guide individual dosing of sunitinib.
Assuntos
Antineoplásicos/farmacocinética , Indóis/metabolismo , Indóis/farmacocinética , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirróis/metabolismo , Pirróis/farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/metabolismo , Citocromo P-450 CYP3A/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , SunitinibeRESUMO
It is previously shown that carriers of the defective allele CYP2C9*3 that leads to impaired sulfonylurea metabolism are at increased sulfonylurea-induced hypoglycemia risk due to diminished drug metabolism, whereas no effect of CYP2C9*2 allele was found. Recently, a polymorphism in P450 oxidoreductase (POR) gene, assigned as POR*28 allele, was associated with increased CYP2C9 activity. The aim of this study was to assess i) the effect of POR*28 allele on sulfonylurea-induced hypoglycemia risk and ii) the association of CYP2C9*2 allele with hypoglycemia risk in non-carriers of POR*28 allele. The study group consisted of 176 patients with diagnosed type 2 diabetes mellitus (T2DM) treated with sulfonylureas, of whom 92 patients had experienced at least one drug-associated hypoglycemic event (cases), while 84 had never experienced a hypoglycemic event (controls). POR*28 allele was detected by use of real-time TaqMan PCR. POR*28 allele was not associated with sulfonyl-urea-induced hypoglycemia. In POR*1/*1 patients, CYP2C9*1/*2 genotype was more common in cases than in controls (32.7 vs. 14.3%, p=0.041). In a model adjusted for age, BMI, duration of T2DM and renal function, and POR*1/*1 entered as a selection variable, CYP2C9*2 allele increased the hypoglycemia risk in response to sulfonylurea (odds ratio: 3.218, p=0.031). In conclusion, our results suggest that POR*28 allele is masking the association of CYP2C9*2 allele with sulfonyl-urea-induced hypoglycemia. Therefore, POR*28 allele is an important source of CYP2C9 activity variability and combined with CYP2C9 gene poly-morphisms may explain individual variability in the effect of sulfonylureas.
Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Hipoglicemia/induzido quimicamente , Hipoglicemia/genética , Hipoglicemiantes/efeitos adversos , NADPH-Ferri-Hemoproteína Redutase/genética , Compostos de Sulfonilureia/efeitos adversos , Alelos , Estudos de Casos e Controles , Citocromo P-450 CYP2C9 , Diabetes Mellitus Tipo 2/complicações , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Fatores de RiscoRESUMO
OBJECTIVE/METHODS: Cushing's disease (CD) is often accompanied by hypertension. CD can be treated surgically and, given the expression of somatostatin subtype 5 and dopamine 2 receptors by corticotroph pituitary adenomas, pharmacologically. Indeed, we recently observed that stepwise medical combination therapy with the somatostatin-analog pasireotide, the dopamine-agonist cabergoline, and ketoconazole (which directly suppresses steroidogenesis) biochemically controlled CD patients and lowered their blood pressure after 80 days. Glucocorticoids (GC) modulate the renin-angiotensin-aldosterone system (RAAS) among others by increasing hepatic angiotensinogen expression and stimulating mineralocorticoid receptors (MR). This study therefore evaluated plasma RAAS components in CD patients before and after drug therapy. In addition, we studied whether cabergoline/pasireotide have direct relaxant effects in angiotensin II (Ang II)-constricted iliac arteries of spontaneously hypertensive rats, with and without concomitant GR/MR stimulation with dexamethasone or hydrocortisone. RESULTS: Baseline concentrations of angiotensinogen were elevated, while renin and aldosterone were low and suppressed, respectively, even in patients treated with RAAS-blockers. This pattern did not change after 80 days of treatment, despite blood pressure normalization, nor after 4 years of remission. In the presence of dexamethasone, pasireotide inhibited Ang II-mediated vasoconstriction. CONCLUSIONS: The low plasma renin concentrations, even under RAAS blockade, in CD may be the consequence of increased GC-mediated MR stimulation and/or the elevated angiotensinogen levels in such patients. The lack of change in RAAS-parameters despite blood pressure and cortisol normalization suggests persisting consequences of long-term exposure to cortisol excess. Finally, pasireotide may have a direct vasodilating effect contributing to blood pressure lowering.