title: Delamanid is not metabolized by Salmonella or human nitroreductases: A possible mechanism for the lack of mutagenicity.
abstract: Nitro-containing compounds such as nitrofuran and nitroimidazole are drugs used for the treatment of infectious diseases. However, many of these nitro-containing drugs are positive in the bacterial reverse mutation assay (Ames test). The recently approved anti-multidrug-resistant tuberculosis (MDR-TB) drug, delamanid (Deltyba™; OPC-67683), a derivative of 4-nitroimidazole, was negative for mutagenicity in the Ames assay. In Salmonella typhimurium, mutagenicity of nitro compounds has been closely associated with the ability of nitroreductase to metabolize (degradation)these compounds. To explore the lack of mutagenicity for delamanid, we examined the initial metabolic rate and mutagenic-specific activity of a series of nitro compounds in S. typhimurium TA100. The order of maximum mutagenic-activity was nitrofuran > 2-nitroimidazole > 5-nitroimidazole ≥ 4-nitroimidazole, which is very similar to the order of initial metabolic rate, i.e., the Pearson's correlation coefficient (r = 0.85) showed a correlation between metabolic rate and mutagenic-activity. No metabolism of delamanid was detected even after 60 h of treatment. In addition, delamanid was not reduced by two human nitroreductases. These facts may explain the absence of genotoxicity of delamanid in both in vitro and in vivo tests.
authors.affiliation: Infectious Diseases Unit, Department of Medical Innovations, Otsuka Pharmaceutical, Tokushima, Japan.
authors.forename: Erina
authors.initials: E
authors.lastname: Hanaki
authors.affiliation: Medical Chemistry Research Laboratories, Otsuka Pharmaceutical, Tokushima, Japan.
authors.forename: Mikayo
authors.initials: M
authors.lastname: Hayashi
authors.affiliation: Pharmaceutical Business Division, Otsuka Pharmaceutical, Tokushima, Japan. Electronic address: Matsumoto.Makoto@otsuka.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Matsumoto
mesh_terms: D000995:Antitubercular Agents / Q000378:metabolism* / Q000633:toxicity; D001426:Bacterial Proteins / Q000378:metabolism*; D001711:Biotransformation; D004269:DNA, Bacterial / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D007700:Kinetics; D016296:Mutagenesis; D009152:Mutagenicity Tests; D009593:Nitroimidazoles / Q000378:metabolism* / Q000633:toxicity; D009601:Nitroreductases / Q000378:metabolism*; D010080:Oxazoles / Q000378:metabolism* / Q000633:toxicity; D010084:Oxidation-Reduction; D018570:Risk Assessment; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D013379:Substrate Specificity
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004269:DNA, Bacterial; D009593:Nitroimidazoles; C516022:OPC-67683; D010080:Oxazoles; D009601:Nitroreductases
keywords: Ames test; DT-Diaphorase (NQO1); Delamanid; Metabolic rate; Mutagen specific activity; Mutagenicity; NQO2; Nitrofuran; Nitroimidazole; Nitroreductase