RT Journal Article SR Electronic T1 Metabolism and Disposition of Ataluren after Oral Administration to Mice, Rats, Dogs, and Humans JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 317 OP 325 DO 10.1124/dmd.119.089391 VO 48 IS 4 A1 Ronald Kong A1 Jiyuan Ma A1 Seongwoo Hwang A1 Elizabeth Goodwin A1 Valerie Northcutt A1 John Babiak A1 Neil Almstead A1 Joseph McIntosh YR 2020 UL http://dmd.aspetjournals.org/content/48/4/317.abstract AB Ataluren is a unique small molecule developed for the treatment of diseases caused by 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. After single oral administration of [14C]ataluren, the overall recovery of radioactivity was ≥93.7%, with approximately 39%, 17%–21%, 12%, and 55% in the urine and 54%, 70%–72%, 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 was 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 after 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, whereas the oxadiazole cleavage products were the major or prominent metabolites in the feces of all species. Overall, the results indicate that phase I metabolism is negligible and that 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. In vivo metabolism and disposition after a single dose of the drug were investigated in mice, rats, dogs, and humans. Phase I metabolism of ataluren was negligible, and the pathway largely involves glucuronidation. No other circulatory conjugation metabolite was detected across investigated species.