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In vitro metabolism of the lignan (-)-grandisin, an anticancer drug candidate, by human liver microsomes.
- Source :
-
Drug testing and analysis [Drug Test Anal] 2015 Sep; Vol. 7 (9), pp. 780-6. Date of Electronic Publication: 2015 Jan 15. - Publication Year :
- 2015
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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.<br /> (Copyright © 2015 John Wiley & Sons, Ltd.)
Details
- Language :
- English
- ISSN :
- 1942-7611
- Volume :
- 7
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Drug testing and analysis
- Publication Type :
- Academic Journal
- Accession number :
- 25594619
- Full Text :
- https://doi.org/10.1002/dta.1743