RESUMEN
Glipizide is a second-generation sulfonylurea antidiabetic drug. It is principally metabolized to inactive metabolites by genetically polymorphic CYP2C9 enzyme. In this study, we investigated the effects of CYP2C9*3 and *13 variant alleles on the pharmacokinetics and pharmacodynamics of glipizide. Twenty-four healthy Korean volunteers (11 subjects with CYP2C9*1/*1, 8 subjects with CYP2C9*1/*3, and 5 subjects with CYP2C9*1/*13) were recruited for this study. They were administered a single oral dose of glipizide 5 mg. The plasma concentration of glipizide was quantified for pharmacokinetic analysis and plasma glucose and insulin concentrations were measured as pharmacodynamic parameters. The results represented that CYP2C9*3 and *13 alleles significantly affected the pharmacokinetics of glipizide. In subjects with CYP2C9*1/*3 and CYP2C9*1/*13 genotypes, the mean AUC0-∞ were increased by 44.8% and 58.2%, respectively (both P < 0.001), compared to those of subjects with CYP2C9*1/*1 genotype, while effects of glipizide on plasma glucose and insulin levels were not significantly different between CYP2C9 genotype groups. In conclusion, individuals carrying the defective CYP2C9*3 and CYP2C9*13 alleles have markedly elevated plasma concentrations of glipizide compared with CYP2C9*1/*1 wild-type.
Asunto(s)
Citocromo P-450 CYP2C9/genética , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Predisposición Genética a la Enfermedad , Glipizida/farmacología , Hipoglucemiantes/farmacología , Administración Oral , Adulto , Alelos , Pueblo Asiatico , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/genética , Femenino , Glipizida/sangre , Glipizida/farmacocinética , Voluntarios Sanos , Humanos , Hipoglucemiantes/sangre , Hipoglucemiantes/farmacocinética , Masculino , Polimorfismo Genético/efectos de los fármacos , República de Corea , Adulto JovenRESUMEN
Oxidative stress contributes to neuronal death in the brain, and neuronal death can cause aging or neurodegenerative disease. Heme oxygenase 1 (HO-1) serves a vital role in the regulation of biological reactions, including oxidative stress associated with reactive oxygen species. In the present study, acerogenin C isolated from the Aceraceae plant Acer nikoense, which is used as a Japanese folk medicine for hepatic disorders and eye diseases. However, there have been no studies on the mechanisms underlying the antineurodegenerative biological activities of acerogenin C. In the present study, acerogenin C demonstrated neuroprotective action against glutamateinduced cell death in hippocampal HT22 cells through the upregulation of HO1 expression. These effects were also associated with nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and the activation of phosphoinositide 3kinase/protein kinase B. Taken together of the efficacy researches, this study determines that the Nrf2/HO1 pathways denotes a biological mark and that acerogenin C might contribute to prevention of neurodegenerative disorders.