PT - JOURNAL ARTICLE AU - Michael Gerisch AU - Roland Heinig AU - Anna Engelen AU - Dieter Lang AU - Peter Kolkhof AU - Martin Radtke AU - Johannes Platzek AU - Kai Lovis AU - Gabriele Rohde AU - Thomas Schwarz TI - Biotransformation of Finerenone, a Novel Nonsteroidal Mineralocorticoid Receptor Antagonist, in Dogs, Rats, and Humans, In Vivo and In Vitro AID - 10.1124/dmd.118.083337 DP - 2018 Jan 01 TA - Drug Metabolism and Disposition PG - dmd.118.083337 4099 - http://dmd.aspetjournals.org/content/early/2018/09/04/dmd.118.083337.short 4100 - http://dmd.aspetjournals.org/content/early/2018/09/04/dmd.118.083337.full AB - Mass balance and biotransformation of finerenone, a nonsteroidal mineralocorticoid receptor antagonist, were investigated in four healthy male volunteers following a single oral administration of 10 mg (78 µCi) of [14C]finerenone and compared with data from studies in dogs and rats. The total recovery of the administered radioactivity was 101% in humans, 94.7% in dogs, and 95.2% in rats. In humans, radioactivity was mainly excreted renally (80%); in rats, it was primarily the biliary/fecal route (76%); and in dogs, excretion was more balanced. Finerenone was extensively metabolized in all species by oxidative biotransformation, with minor amounts of unchanged drug in excreta (humans: 1%; dogs, rats: < 9%). In vitro studies suggested cytochrome P450 3A4 was the predominant enzyme involved in finerenone metabolism in humans. Primary metabolic transformation involved aromatization of the dihydronaphthyridine moiety to metabolite M1 as a major clearance pathway and a second oxidative pathway leading to M4. These were both prone to further oxidative biotransformation reactions. Naphthyridine metabolites (M1-M3) were the dominant metabolites identified in human plasma, with no on-target pharmacological activity. In dog plasma, finerenone and metabolite M2 comprised the major components; finerenone accounted almost exclusively for drug-related material in rat plasma. For metabolites M1-M3, axial chirality was observed, represented by two atropisomers (e.g., M1a and M1b). Analysis of plasma and excreta showed one atropisomer (a-series, >79%) of each metabolite predominated in all three species. In summary, the present study demonstrates that finerenone is cleared by oxidative biotransformation, mainly via naphthyridine derivatives.