In vitro metabolism study of the bioactive lignan (-)-Grandisin

GB Messiano; RA da S Santos; LS Ferreira; RA Simões; MJ Kato; NP Lopes; MT Pupo; ARM Oliveira

doi:10.1055/s-0032-1320670

Planta Medica, Table of Contents

In vitro metabolism study of the bioactive lignan (-)-Grandisin

GB Messiano ¹, RA da S Santos ², LS Ferreira ¹, RA Simões ¹, MJ Kato ³, NP Lopes ¹, MT Pupo ¹, ARM Oliveira ²

¹Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, 14040–903, Ribeirão Preto, SP, Brazil
²Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, 14040–901, Ribeirão Preto, SP, Brazil
³Instituto de Química, Universidade de São Paulo, 05513–970, São Paulo, SP, Brazil

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±0.034µmol/mg protein/h and 8.99±0.488µM, respectively. In addition, the formation of dihydro-grandisin, characterized by GC-MS, by mammalian systems indicated the involvement of a CYP450 enzyme type.