title: In vitro metabolism study of the promising anticancer agent the lignan (-)-grandisin.
abstract: The lignan (-)-grandisin has shown important pharmacological activities, such as citotoxicity and antiangiogenic, antibacterial and trypanocidal activities. So, it has been considered as a potential drug candidate. In the early drug development process, drug metabolism is one of the main parameters that should be evaluated; therefore, the biotransformation of this lignan by rat liver microsomes was investigated for the first time. In order to perform the biotransformation study and to determine the kinetic parameters, a simple, sensitive and selective HPLC method was developed and fully validated. After method validation, the biotransformation study was accomplished and the kinetic parameters were determined. The biotransformation study obeyed the Michaelis-Menten kinetics. The V(max) and K(m) were 1.46 ± 0.034 μmol/mg protein/h and 8.99 ± 0.488 μM, respectively. In addition, the formation of dihydro-grandisin, characterized by GC-MS, by mammalian systems indicated the involvement of a CYP450 enzyme type.
authors.affiliation: Departamento de Ciências Farmacêuticas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, 14040-903, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Gisele Baraldi
authors.initials: GB
authors.lastname: Messiano
authors.forename: Renan Augusto da Silva
authors.initials: RA
authors.lastname: Santos
authors.forename: Leandro De Santis
authors.initials: Lde S
authors.lastname: Ferreira
authors.forename: Rodrigo Almeida
authors.initials: RA
authors.lastname: Simões
authors.forename: Valquíria Aparecida Polisel
authors.initials: VA
authors.lastname: Jabor
authors.forename: Massuo Jorge
authors.initials: MJ
authors.lastname: Kato
authors.forename: Norberto Peporine
authors.initials: NP
authors.lastname: Lopes
authors.forename: Mônica Tallarico
authors.initials: MT
authors.lastname: Pupo
authors.forename: Anderson Rodrigo Moraes
authors.initials: AR
authors.lastname: de Oliveira
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism* / Q000493:pharmacokinetics; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D005663:Furans / Q000737:chemistry* / Q000378:metabolism* / Q000493:pharmacokinetics; D007700:Kinetics; D017705:Lignans / Q000737:chemistry* / Q000378:metabolism* / Q000493:pharmacokinetics; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000970:Antineoplastic Agents; D005663:Furans; D017705:Lignans; C074346:grandisin