title: In vitro characterization of rosiglitazone metabolites and determination of the kinetic parameters employing rat liver microsomal fraction.
abstract: Rosiglitazone (RSG), a thiazolidinedione antidiabetic drug, is metabolized by CYP450 enzymes into two main metabolites: N-desmethyl rosiglitazone (N-Dm-R) and ρ-hydroxy rosiglitazone (ρ-OH-R). In humans, CYP2C8 appears to have a major role in RSG metabolism. On the other hand, the in vitro metabolism of RSG in animals has not been described in literature yet. Based on these concerns, the kinetic metabolism study of RSG using rat liver microsomal fraction is described for the first time. Maximum velocity (V (max)) values of 87.29 and 51.09 nmol/min/mg protein were observed for N-Dm-R and ρ-OH-R, respectively. Michaelis-Menten constant (K(m)) values were of 58.12 and 78.52 μM for N-Dm-R and ρ-OH-R, respectively. Therefore, these results demonstrated that this in vitro metabolism model presents the capacity of forming higher levels of N-Dm-R than of ρ-OH-R, which also happens in humans. Three other metabolites were identified employing mass spectrometry detection under positive electrospray ionization: ortho-hydroxy-rosiglitazone (ο-OH-R) and two isomers of N-desmethyl hydroxy-rosiglitazone. These metabolites have also been observed in humans. The results observed in this study indicate that rats could be a satisfactory model for RSG metabolism.
authors.affiliation: Departamento de Física e Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, 14040-903, Brazil.
authors.forename: Leandro Augusto
authors.initials: LA
authors.lastname: Calixto
authors.forename: Anderson Rodrigo Moraes
authors.initials: AR
authors.lastname: de Oliveira
authors.forename: Valquíria Aparecida Polisel
authors.initials: VA
authors.lastname: Jabor
authors.forename: Pierina Sueli
authors.initials: PS
authors.lastname: Bonato
mesh_terms: D000818:Animals; D003640:Dealkylation; D007004:Hypoglycemic Agents / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012044:Regression Analysis; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000378:metabolism*
chemical_list: D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000077154:Rosiglitazone