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In vitro metabolism study of the promising anticancer agent the lignan (−)-grandisin

2012; Elsevier BV; Volume: 72; Linguagem: Inglês

10.1016/j.jpba.2012.08.028

1873-264X

Gisele B. Messiano, Renan Augusto da Silva Santos, Leandro De Santis Ferreira, Rodrigo Almeida Simões, Valquíria Aparecida Polisel Jabor, Massuo J. Kato, Norberto Peporine Lopes, Mônica Tallarico Pupo, Anderson Rodrigo Moraes de Oliveira,

Pharmacogenetics and Drug Metabolism

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 Vmax and Km 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.