RESUMO
INTRODUCTION: Antiepileptic drugs (AEDs) are used for the seizures control in patients with epilepsy, however 20-30% of epileptic patients are drug resistant. Several factors contributing to the variability of the AEDs response, and this variability can be partially attributed to the presence of sequence variations (polymorphisms) in genes encoding enzymes involved in the AEDs metabolism. AIM: To describe the polymorphisms in genes that encoding for proteins involved in the metabolism of some of the major AEDs, focusing on enzymes cytochrome P450 (CYP450). DEVELOPMENT: There are some polymorphisms in genes encoding proteins involved in drug metabolism, particularly enzymes of superfamily CYP450, that are already considered of clinical utility in the therapeutic management. These genetic variants contribute to the variability of the activity of metabolizing enzymes, which in turn influencing the poor or inadequate therapeutic response, as well as in the occurrence of adverse effects. CONCLUSIONS: The identification of interindividual variability in the response to AEDs may allow the personalized treatment with the aim of maximize the efficiency and minimize risk, regardless of the clinical variability and adverse effects could be manifest in a minority of the patients.
TITLE: Farmacogenetica y metabolismo de farmacos antiepilepticos: implicacion de variantes geneticas en citocromos P450.Introduccion. Los farmacos antiepilepticos (FAE) son la base para el control de las crisis en pacientes con epilepsia; sin embargo, se conoce que el 20-30% de los pacientes son farmacorresistentes. Son diversos los factores que contribuyen a la variabilidad de la respuesta a los FAE, y esta variabilidad puede atribuirse, al menos en parte, a la presencia de polimorfismos (variaciones de la secuencia) en genes que codifican para enzimas involucradas en el metabolismo de los FAE. Objetivo. Describir las variaciones de la secuencia en genes que codifican para proteinas implicadas en el metabolismo de algunos de los principales FAE, con enfasis en las enzimas citocromo P450 (CYP450). Desarrollo. Existen algunos polimorfismos en genes que codifican para proteinas involucradas en el metabolismo de farmacos, particularmente enzimas de la superfamilia CYP450, que se consideran ya de utilidad clinica en el manejo terapeutico. La presencia de estas variantes geneticas contribuye a la variabilidad de la actividad de enzimas metabolizadoras, lo que, a su vez, influye en la pobre o inadecuada respuesta terapeutica, e incluso en la aparicion de efectos adversos. Conclusiones. La identificacion de la variabilidad interindividual en la respuesta a los diversos FAE puede permitir la individualizacion del tratamiento con la intencion de maximizar su eficacia y minimizar el riesgo, independientemente de que la variabilidad clinica y los efectos adversos se presenten en una minoria de pacientes.
Assuntos
Anticonvulsivantes/farmacocinética , Biotransformação/genética , Sistema Enzimático do Citocromo P-450/genética , Variação Genética , Hidrocarboneto de Aril Hidroxilases/genética , Hidrocarboneto de Aril Hidroxilases/fisiologia , Barbitúricos/farmacocinética , Benzodiazepinonas/farmacocinética , Carbamazepina/farmacocinética , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP2C9 , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/fisiologia , Sistema Enzimático do Citocromo P-450/classificação , Sistema Enzimático do Citocromo P-450/fisiologia , Resistência a Medicamentos/genética , Genótipo , Humanos , Inativação Metabólica/genética , Isoenzimas/genética , Polimorfismo Genético/genética , Ácido Valproico/farmacocinéticaRESUMO
This study examined the effects of peripheral-type benzodiazepine receptors in the forced swimming test. PK 11195 (1-(2-chloro-phenyl)-N-methyl-N-(1-methylpropyl)-1-isoquinoline carboxamide) and Ro5-4864 (7-chloro-5-(4-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepine-2-one) were i.p. injected in mice, according to an acute (1 or 24 h) and a repeated (14 days) schedule. Pretreatment with the agonist, Ro5-4864, significantly reduced immobility time 1 h after treatment but not 24 h after it, whereas the antagonist, PK11195, did not interfere with the test parameters. Nevertheless, PK11195 pretreatment inhibited the Ro5-4864 antidepressant-like effect. Animals repeatedly treated with Ro5-4864 had a similar profile of action with no sign of motor impairment or locomotor activation as evaluated in the rota-rod and open-field tests, respectively. Aminoglutethimide pretreatment, which blocks the early step of steroid synthesis, inhibited the antidepressant-like effect of Ro5-4864. The present findings suggest an antidepressant-like profile for the benzodiazepine, Ro5-4864, that seems to involve steroid synthesis as underlying mechanism.
Assuntos
Antidepressivos/farmacocinética , Benzodiazepinas/farmacocinética , Benzodiazepinonas/farmacocinética , Receptores de GABA-A/efeitos dos fármacos , Natação , Aminoglutetimida/administração & dosagem , Aminoglutetimida/farmacocinética , Animais , Antidepressivos/administração & dosagem , Benzodiazepinas/administração & dosagem , Benzodiazepinas/antagonistas & inibidores , Benzodiazepinonas/administração & dosagem , Agonistas de Receptores de GABA-A , Imipramina/administração & dosagem , Imipramina/farmacocinética , Imobilização , Injeções Intraperitoneais , Isoquinolinas/administração & dosagem , Isoquinolinas/farmacocinética , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Sistema Nervoso Periférico/química , Teste de Desempenho do Rota-Rod , Fatores de TempoRESUMO
The effects of chronic benzodiazepine (BZD) treatment on rat peripheral-type benzodiazepine receptors (PBR) were studied. Five days treatment with the PBR ligands RO 5-4864 or diazepam (DZ) up-regulates kidney PBR. In contrast clonazepam, a specific central-type BZD receptor ligand, did not alter 3H-RO 5-4864 binding. Fourteen days administration of DZ produced an up-regulation of kidney and heart PBR and a down-regulation of testicular PBR. The results suggest that chronic BZD exposure differentially regulates PBR in peripheral organs.