PT - JOURNAL ARTICLE AU - Ronald Kong AU - Jiyuan Ma AU - Seongwoo Hwang AU - Elizabeth Goodwin AU - Valerie Northcutt AU - John Babiak AU - Neil Almstead AU - Joseph McIntosh TI - Metabolism and Disposition of Ataluren following Oral Administration to Mice, Rats, Dogs, and Humans AID - 10.1124/dmd.119.089391 DP - 2020 Jan 01 TA - Drug Metabolism and Disposition PG - dmd.119.089391 4099 - http://dmd.aspetjournals.org/content/early/2020/01/24/dmd.119.089391.short 4100 - http://dmd.aspetjournals.org/content/early/2020/01/24/dmd.119.089391.full AB - Ataluren is a unique small molecule developed for the treatment of diseases due to presence of nonsense mutations, which result in premature termination of ribosomal translation and lack of full-length protein production. This study investigated the in vivo metabolism and disposition of ataluren in mice, rats, dogs and humans. Following single oral administration of [14C] ataluren, the overall recovery of radioactivity was ≥ 93.7%, with approximately 39%, 17% to 21%, 12%, and 55% in the urine, and 54%, 70%, 80%, and 47% in the feces from intact mice, rats, dogs, and humans, respectively. In bile-duct cannulated (BDC) rats, approximately 10%, 7%, and 82% of the dose were recovered in the urine, feces, and bile, respectively, suggesting that biliary secretion was a major route for the elimination of ataluren in the rats. Ataluren was extensively metabolized following oral administration and the metabolic profiles of ataluren were quantitatively similar across all species. Unchanged ataluren was the dominant radioactive component in plasma. Ataluren acyl glucuronide was the most prominent metabolite in plasma of all species and the dominant metabolite in BDC rat bile and human urine, while the oxadiazole cleavage products were the major or prominent metabolites in the feces of all species. Overall, the results indicate that, unlike most small molecules, phase I metabolism is negligible, and the pathway largely involves glucuronidation. No other circulatory conjugation metabolite was detected across investigated species.SIGNIFICANCE STATEMENT Ataluren is a novel carboxylic acid containing small molecule drug for treating nonsense mutation Duchenne muscular dystrophy (nmDMD). In vivo metabolism and disposition after a single dose of the drug were investigated in mice, rats, dogs and humans. Unlike most small molecules, phase I metabolism of ataluren was negligible, and the pathway largely involves glucuronidation. No other circulatory conjugation metabolite was detected across investigated species.