In vitro metabolism of the lignan (−)‐grandisin,an anticancer drug candidate,by human liver microsomes |
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| Authors: | Thiago Barth Maísa Daniela Habenschus Fernanda Lima Moreira Leandro De Santis Ferreira Norberto Peporine Lopes Anderson Rodrigo Moraes de Oliveira |
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| Affiliation: | 1. Núcleo de Pesquisa em Produtos Naturais e Sintéticos (NPPNS), Faculdade de Ciências Farmacêuticas de Ribeir?o Preto, Universidade de S?o Paulo, Ribeir?o Preto, SP, Brazil;2. Curso de Farmácia, Universidade Federal do Rio de Janeiro, Macaé‐RJ, Brazil;3. Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeir?o Preto, Universidade de S?o Paulo, Ribeir?o Preto‐SP, Brazil;4. Faculdade de Ciências Farmacêuticas de Ribeir?o Preto, Universidade de S?o Paulo, Ribeir?o Preto, Brazil;5. Lychnoflora Pesquisa & Desenvolvimento em Produtos Naturais LTDA, Vila Virgínia, Ribeir?o Preto‐SP, Brazil |
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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. Copyright © 2015 John Wiley & Sons, Ltd. |
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| Keywords: | (− )‐grandisin human liver microsomes in vitro metabolism metabolite identification |
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