In vitro metabolism of the lignan (-)-grandisin, an anticancer drug candidate, by human liver microsomes.
Drug Test Anal
; 7(9): 780-6, 2015 Sep.
Article
en En
| MEDLINE
| ID: mdl-25594619
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 (Vmax ) was 3.96 ± 0.18 µmol/mg protein/h, and the Michaelis-Menten constant (Km ) was 8.23 ± 0.99 µM. 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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Microsomas Hepáticos
/
Lignanos
/
Furanos
/
Antineoplásicos
Límite:
Humans
Idioma:
En
Revista:
Drug Test Anal
Asunto de la revista:
FARMACOLOGIA
Año:
2015
Tipo del documento:
Article
País de afiliación:
Brasil