Evaluation of covalent binding of flutamide and its risk assessment using 19F-NMR.

This study aimed to provide a practical approach toward the risk assessment of hepatotoxicity induced by covalent binding before candidate selection.We focused on flutamide because it contains a trifluoromethyl group that shows a strong singlet peak by 19F-nuclear magnetic resonance (NMR) spectrometry. The covalent binding of flutamide was evaluated using quantitative NMR and its risk for hepatotoxicity was assessed by estimating the reactive metabolite (RM) burden, an index that reflects the body burden associated with reactive metabolite exposure by determining the extent of covalent binding, clinical dose, and in vivo clearance. The extent of covalent binding and RM burden was 296 pmol/mg/h and 37.9 mg/day, respectively. Flutamide was categorised as high risk with an RM burden >10 mg/day consistent with its clinical hepatotoxicity.These results indicate that a combination of covalent binding assay using 19F-NMR and RM burden is useful for the risk assessment of reactive metabolites without using radiolabelled compounds.
PMID: 32876521 [PubMed - as supplied by publisher]

Source: Xenobiotica - September 1, 2020 Category: Research Authors: Kakutani N, Iwai T, Ohno Y, Kobayashi S, Nomura Y Tags: Xenobiotica Source Type: research