@article {Gerisch1546, author = {Michael Gerisch and Roland Heinig and Anna Engelen and Dieter Lang and Peter Kolkhof and Martin Radtke and Johannes Platzek and Kai Lovis and Gabriele Rohde and Thomas Schwarz}, title = {Biotransformation of Finerenone, a Novel Nonsteroidal Mineralocorticoid Receptor Antagonist, in Dogs, Rats, and Humans, In Vivo and In Vitro}, volume = {46}, number = {11}, pages = {1546--1555}, year = {2018}, doi = {10.1124/dmd.118.083337}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {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 of metabolite M1 as a major clearance pathway with a second oxidative pathway leading to M4. These were both prone to further oxidative biotransformation reactions. Naphthyridine metabolites (M1{\textendash}M3) were the dominant metabolites identified in human plasma, with no on-target pharmacological activity. In dog plasma, finerenone and metabolite M2 constituted the major components; finerenone accounted almost exclusively for drug-related material in rat plasma. For metabolites M1{\textendash}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.}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/46/11/1546}, eprint = {https://dmd.aspetjournals.org/content/46/11/1546.full.pdf}, journal = {Drug Metabolism and Disposition} }