Biotransformation of Finerenone, a Novel Nonsteroidal Mineralocorticoid Receptor Antagonist, in Dogs, Rats, and Humans, In Vivo and In Vitro.
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Gerisch M, Heinig R, Engelen A, Lang D, Kolkhof P, Radtke M, Platzek J, Lovis K, Rohde G, Schwarz T
Biotransformation of Finerenone, a Novel Nonsteroidal Mineralocorticoid Receptor Antagonist, in Dogs, Rats, and Humans, In Vivo and In Vitro.
Drug Metab Dispos. 2018 Nov;46(11):1546-1555. doi: 10.1124/dmd.118.083337. Epub 2018 Aug 31.
- PubMed ID
- 30171161 [ View in PubMed]
- 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 muCi) of [(14)C]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-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-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.
DrugBank Data that Cites this Article
- Drugs
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Finerenone Cytochrome P450 1A1 Protein Humans UnknownSubstrateDetails Finerenone Cytochrome P450 2C8 Protein Humans UnknownSubstrateDetails Finerenone Cytochrome P450 3A4 Protein Humans UnknownSubstrateDetails - Drug Reactions
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