Genotoxicity assessment of the antiepileptic drug AMP397, an Ames-positive aromatic nitro compound

AMP397 is a novel antiepileptic agent and the first competitive AMPA antagonist with high receptor affinity, good in vivo potency, and oral activity. AMP397 has a structural alert (aromatic nitro group) and was mutagenic in Salmonella tymphimurium strains TA97a, TA98 and TA100 without S9, but negative in the nitroreductase-deficient strains TA98NR and TA100NR. The amino derivative of AMP397 was negative in wild-type strains TA98 and TA100. AMP397 was negative in a mouse lymphoma tk assay, which included a 24 h treatment without S9. A weak micronucleus induction in vitro was found at the highest concentrations tested in V79 cells with S9. AMP397 was negative in the following in vivo studies, which included the maximum tolerated doses of 320 mg/kg in mice and 2000 mg/kg in rats: Muta(TM)Mouse assay in colon and liver (5 x 320 mg/kg) at three sampling times (3, 7 and 31 days after the last administration); DNA binding study in the liver of mice and rats after a single treatment with [C-14]-AMP397; comet assay (1 x 2000 mg/kg) in jejunum and liver of rats, sampling times 3 and 24 h after administration; micronucleus test (2 x 320 mg/kg) in the bone marrow of mice, sampling 24 h after the second administration. Based on these results, it was concluded that AMP397 has no genotoxic potential in vivo. In particular, no genotoxic metabolite is formed in mammalian cells, and, if formed by intestinal bacteria, is unable to exert any genotoxic activity in the adjacent intestinal tissue. These data were considered to provide sufficient safety to initiate clinical development of the compound. (C) 2002 Elsevier Science B.V. All rights reserved.