Subchronic Toxicity, Metabolism, and Pharmacokinetics of the Aminobenzamide Anticonvulsant Ameltolide (LY2O1 116) in Rhesus Monkeys

Studies were undertaken to define the subchronic toxicologicprofile of ameltolide, an aminobenzamide anticonvulsant, inyoung adult rhesus monkeys. Daily doses of ameltolide, dissolvedin 10% aqueous acacia, were administered orally via nasogastricintubation at dosages of 5, 10, 20, 45, and 100 mg/kg. Deathsoccurred in two monkeys, one each at 45 and 100 mg/kg, whichwere directly attributable to the effects of the compound. Theexact cause of death in these monkeys was not readily apparent.A third monkey (100 mg/kg) was killed moribund on Day 82 ofthe study due to conditions not directly related to treatment.Clinical signs in monkeys treated with 100 mg/kg included convulsions, diarrhea, weakness, inappetance, vomition, and ataxia.Plasma concentrations of the N-acetyl metabolite of ameltolidewere greater than parent drug concentrations by one to two ordersof magnitude. Mean area under the plasma-time curve (AUC) valuesfor ameltolide were larger than expected at doses of 20 mg/kgor greater, while AUC values for the metabolite were less thanexpected at 45 and 100 mg/kg. These findings suggest a saturationof metabolism and/or excretion at the two higher doses. Similarnonlinearity was seen with mean peak concentrations for bothparent and metabolite. No specific target organ toxicity wasfound on histological evaluation of tissue sections. Methemoglobinconcentration was increased in monkeys given 45 or 100 mg ameltolide/kg.This change was not considered to be toxicologically importantas there were no corroborative clinical, gross, or histopathologicalfindings. A meltolide administered by nasogastric intubationat doses up to 20 mg/kg/day for 3 months did not cause any toxicologicallyimportant alterations in rhesus monkeys.