Disposition, profiling and identification of emixustat and its metabolites in humans

1. Emixustat is a small molecule that potently inhibits retinal pigment epithelium 65 isomerohydrolase. Emixustat is in clinical development for the treatment of various retinopathies (i.e. Stargardt disease and diabetic retinopathy). 2. A human absorption, distribution, metabolism, and excretion (ADME) study was conducted with a single dose of [¹⁴C]-emixustat in healthy male subjects. Total ¹⁴C content in plasma, urine, and faeces was determined using accelerator mass spectrometry (AMS), and metabolic profiles in pooled plasma and urine were investigated by both HPLC-AMS and 2D LC-MS/MS. 3. After a single, oral 40-mg dose of [¹⁴C]-emixustat, recovery of total ¹⁴C was nearly complete within 24 h. Urine was the major route of ¹⁴C elimination; accounting for > 90% of the administered dose. 4. Biotransformation of emixustat occurred primarily at two structural moieties; oxidation of the cyclohexyl moiety and oxidative deamination of the 3R-hydroxypropylamine, both independently and in combination to produce secondary metabolites. Metabolite profiling in pooled plasma samples identified 3 major metabolites: ACU-5124, ACU-5116 and ACU-5149, accounting for 29.0%, 11.5%, and 10.6% of total ¹⁴C, respectively. Emixustat was metabolized in human hepatocytes with unchanged emixustat accounting for 33.7% of sample radioactivity and predominantly cyclohexanol metabolites observed.