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

(−)‐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 µmol/mg protein/h, and the Michaelis‐Menten constant (K m ) 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. Copyright © 2015 John Wiley & Sons, Ltd.