In vitro metabolism of the lignan (-)-grandisin, an anticancer drug candidate, by human liver microsomes

Author(s)

Barth, Thiago ^{[1, 2]} ; Habenschus, Maisa Daniela ^[3] ; Moreira, Fernanda Lima ^[4] ; Ferreira, Leandro De Santis ^[5] ; Lopes, Norberto Peporine ^[1] ; Moraes de Oliveira, Anderson Rodrigo ^[3]

Affiliation

^[1] Univ Sao Paulo, Nucleo Pesquisa Prod Nat & Sintet, Fac Ciencias Farmaceut Ribeirao Preto, BR-14040903 Ribeirao Preto, SP - Brazil

^[2] Univ Fed Rio de Janeiro, Curso Farm, BR-27930560 Macae, RJ - Brazil

^[3] Univ Sao Paulo, Fac Filosofia Ciencias & Letras Ribeirao Preto, Dept Quim, BR-14040901 Ribeirao Preto, SP - Brazil

^[4] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, BR-14040903 Ribeirao Preto, SP - Brazil

^[5] Lychnoflora Pesquisa & Desenvolvimento Prod Nat L, BR-14030090 Ribeirao Preto, SP - Brazil

• Document type: Journal article
• Source: DRUG TESTING AND ANALYSIS; v. 7, n. 9, p. 780-786, SEP 2015.
• Web of Science Citations: 6

Abstract

(-)-grandisin is a tetrahydrofuran lignan that displays important biological properties, such as trypanocidal, anti-inflammatory, cytotoxic, and antitumor activities, suggesting its utility as a potential drug candidate. One important step in drug development is metabolic characterization and metabolite identification. To perform a biotransformation study of (-)-grandisin and to determine its kinetic properties in humans, a high performance liquid chromatography (HPLC) method was developed and validated. After HPLC method validation, the kinetic properties of (-)-grandisin were determined. (-)-grandisin metabolism obeyed Michaelis-Menten kinetics. The maximal reaction rate (V-max) was 3.96 +/- 0.18 mu mol/mg protein/h, and the Michaelis-Menten constant (K-m) was 8.23 +/- 0.99M. In addition, the structures of the metabolites derived from (-)-grandisin were characterized via gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) analysis. Four metabolites, 4-O-demethylgrandisin, 3-O-demethylgrandisin, 4,4-di-O-demethylgrandisin, and a metabolite that may correspond to either 3,4-di-O-demethylgrandisin or 3,5-di-O-demethylgrandisin, were detected. CYP2C9 isoform was the main responsible for the formation of the metabolites. These metabolites have not been previously described, demonstrating the necessity of assessing (-)-grandisin metabolism using human-derived materials. Copyright (c) 2015 John Wiley \& Sons, Ltd. (AU)

• FAPESP's process: 09/51812-0 - Development of a platform for the study of in vitro and in vivo metabolism of natural products, a need for pre-clinical testing system
• Grantee: Norberto Peporine Lopes
• Support type: BIOTA-FAPESP Program - Thematic Grants
• FAPESP's process: 13/17658-9 - Development and validation of chromatographic and electrophoretic methods for subsequent application in studies of in vitro metabolism and biotransformation - phase 2
• Grantee: Anderson Rodrigo Moraes de Oliveira
• Support type: Regular Research Grants