RESUMO
Carvedilol, a drug available as a racemic mixture, is metabolised into hydroxyphenylcarvedilol (OHC) by CYP2D6 and O-desmethylcarvedilol (DMC) by CYP2C9 followed by conjugation to glucuronides. In contrast to other ß-adrenergic receptor antagonists, carvedilol does not induce insulin resistance or worsen glycaemic control in diabetic hypertensive patients. This study aims to investigate the implications of type 2 diabetes (T2DM) on the pharmacokinetics of carvedilol enantiomers using an integrated population pharmacokinetic modelling approach. In total, 14 T2DM patients with good glycaemic control receiving standard doses of metformin and glibenclamide were evaluated along with a control group of 13 healthy subjects. Serial blood samples were collected up to 24h after administration of a single 25mg dose of racemic carvedilol. A multicompartmental population pharmacokinetic model describing the enantioselective disposition of the parent compound, OHC and DMC was developed in NONMEM v7.2. Even though data are limited, it appears that despite inhibition of CYP2C9 due to long-term glibenclamide administration to T2DM patients, overall no differences are observed in the total clearance of carvedilol when compared to healthy subjects (43.1 vs. 45.9L/h for (S)-(-)-carvedilol and 29.0 vs. 33.1L/h for (R)-(+)-carvedilol). These results provide evidence of a compensatory mechanism for the inhibition of CYP2C9, with higher contribution of CYP2D6 activity to the elimination of carvedilol. Consequently, no dose adjustment is recommended for carvedilol in T2DM patients receiving glibenclamide and metformin.
Assuntos
Antagonistas Adrenérgicos beta/metabolismo , Antagonistas Adrenérgicos beta/farmacocinética , Carbazóis/metabolismo , Carbazóis/farmacocinética , Diabetes Mellitus Tipo 2/metabolismo , Propanolaminas/metabolismo , Propanolaminas/farmacocinética , Antagonistas Adrenérgicos beta/administração & dosagem , Adulto , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Carbazóis/administração & dosagem , Carvedilol , Citocromo P-450 CYP2C9/metabolismo , Inibidores do Citocromo P-450 CYP2C9/administração & dosagem , Citocromo P-450 CYP2D6/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Glibureto/administração & dosagem , Voluntários Saudáveis , Humanos , Hipoglicemiantes/administração & dosagem , Masculino , Metformina/administração & dosagem , Pessoa de Meia-Idade , Propanolaminas/administração & dosagem , EstereoisomerismoRESUMO
Introducción: la existencia de variaciones interindividuales en la respuesta a los medicamentos es multifactorial e incluye la genética y el medio ambiente por tanto, en la práctica clínica es importante considerar los efectos de los medicamentos biotransformados por enzimas polimórficas como el citocromo P4502C9 (CYP2C9), que metaboliza aproximadamente el 16 por ciento de los fármacos de uso habitual, de forma tal, que la asociación entre los estudios de farmacovigilancia y farmacogenética permitirían relacionar algunos fármacos con riesgo de reacciones adversas y por tanto, racionalizar la farmacoterapéutica. Objetivo: describir la aparición de las reacciones adversas a fármacos metabolizados por el CYP2C9, en pacientes de un consultorio médico. Métodos: se realizó un estudio observacional, descriptivo, transversal en los 143 pacientes de un Consultorio Médico del Policlínico Joaquín Albarrán, que en el periodo de estudio consumían fármacos metabolizados por el CYP2C9. Resultados: se detectaron 43 reacciones adversas, el 88.4 por ciento vinculadas a antiinflamatorios no esteroideos, entre ellos al ibuprofeno correspondió el 65.1 por ciento de las mismas. La edad y el sexo no influyeron en la aparición de las reacciones. El 55.8 por ciento de las reacciones clasificaron como leves. Conclusiones: la quinta parte de los pacientes que presentaron reacciones adversas consumieron fármacos metabolizados por el CYP2C9, resultando insuficientes para predecir la respuesta a los medicamentos; variables tradicionalmente aceptadas, así como la edad y el sexo; deben ser considerados los factores que influyen sobre la capacidad de biotransformación de las enzimas metabolizadoras de fármacos, durante el proceso de prescripción(AU)
Introduction: the existence of variations in the drug response among individuals is multifactoral and includes genetics and environment; so it is important for clinical practice to consider the effects of drugs that are biologically transformed by polymorphic enzymes such as cytochrome P4502C9 (CYP2C9), which roughly metabolizes 16 percent of regularly used drugs so that the association of pharmacovigilance and pharmacogenetic studies would allow relating some drugs with possibilities of adverse reactions, and therefore, being more rational in drug therapy. Objective: to describe the occurrence of adverse reactions to drugs metabolized by CYP2C9 in patients from a physician's office. Methods: observational, descriptive and cross-sectional study conducted in 143 patients from a physician's office of Joaquin Albarran polyclinics, who took CYP2C9-metabolized drugs in the study period. Results: there were detected 43 adverse reactions, being 88.4 por ciento of them linked to non-steroidal anti-inflammatory drugs; Ibuprofen accounted for 65.1 percent of them. Age and sex did not influence the occurrence of reactions. In the group;, 55.8 percent of reactions were rated as mild. Conclusions: the fifth part of patients who showed adverse reactions had taken cytochrome CYP2C9-metabolized drugs, they were not sufficient to predict response to traditionally accepted variable drugs as well as age and sex. The factors having an impact on the capacity of biotransformation of drug-metabolizing enzymes should be taken into consideration at the time of prescription of a drug(AU)