Human absorption, distribution, metabolism, excretion, and reaction phenotyping of ervogastat (PF-06865571), a diacylglycerol O-acyltransferase 2 inhibitor

C]ervogastat after oral administration was 79.0% ± 16.7%, with 48.9% ± 16.3% in the urine and 30.1% ± 2.9% in the feces. Ervogastat metabolites observed in human plasma, urine and feces generally can be assigned as originating from 1 of 4 primary metabolic pathways: amide bond hydrolysis (M2); tetrahydrofuran oxidation (M4/M5); O-de-ethylation (M1); and direct glucuronidation (584). The major circulating drug-related components were ervogastat (43.8%), M2 (36.6%), and M6 (11.3%). The major drug-related components detected in urine were M2 (24.9%) and coeluting M6 (des-ethyl sulfate), M7 (des-ethyl amide hydrolysis) and 584 (11.4%). In the feces, the predominant drug-related products were coeluting M4 and 426 (10.0%), M2 (7.0), M7 (6.3%), and M1 (4.5%). Reaction phenotyping was carried out using a subsequent qualitative followed by quantitative approach identifying CYP3A metabolism as the predominant route of in vitro metabolism. As assignment of metabolic pathways in the hADME study was complicated by chromatographically coeluting metabolites or metabolites arising from multiple possible primary pathways, fractional clearance ranges were derived by assigning metabolites to only one primary pathway at a time to represent a potential permutation followed by evaluation of all possible permutations. This novel approach allowed us to overcome the aforementioned confounding issues and, along with in vitro chemical inhibition results, permitted the assignment of the various metabolic pathways and enzymes involved in the metabolism of ervogastat. SIGNIFICANCE STATEMENT: This study provides a comprehensive and quantitative overview of the disposition, clearance pathways, and pharmacokinetics in humans of ervogastat, a potent and selective inhibitor of diacylglycerol-O-acyltransferase-2 for the treatment of metabolic dysfunction-associated steatohepatitis with liver fibrosis.