Biotransformation of Finerenone, a Novel Nonsteroidal Mineralocorticoid Receptor Antagonist, in Dogs, Rats, and Humans, In Vivo and In Vitro

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 Ci) of [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.

Population Pharmacokinetic and Exposure–Response Analysis of Finerenone: Insights Based on Phase IIb Data and Simulations to Support Dose Selection for Pivotal Trials in Type 2 Diabetes with Chronic Kidney Disease

“…No clear effects on AUC or C max were seen in participants with mild hepatic impairment [9]. Crossover studies assessed the mass balance, absolute bioavailability, and effects of erythromycin, verapamil, and gemfibrozil on the systemic exposure of finerenone, complemented by in vitro studies [10,11].…”

Enantioselective Total Synthesis of (−)‐Finerenone Using Asymmetric Transfer Hydrogenation

“…Mortality rates due to heart failure can be markedly reduced by treatment with certain steroids (spironolactone ( 1 ) and eplerenone ( 2 )) which block the mineralocorticoid receptor (MR) (Figure 1). [1] However, their clinical use is limited due to the significant side effects they can cause for example, hyperkalemia and worsening of kidney function [2] and so new MR antagonists are required [3] . As an alternative, it has been reported that 1,4‐dihydropyridines (DHPs), a compound class known for its Ca 2+ channel modulating activity, [4] can act as MR antagonists in vitro [5] .…”

Magnetic Nanoparticles with Dual Surface Functions—Efficient Carriers for Metalloporphyrin-Catalyzed Drug Metabolite Synthesis in Batch and Continuous-Flow Reactors

“…In vitro and in vivo studies also showed that the major metabolite of amlodipine is the dehydrogenated pyridine analogue (2, Figure 1) which is primarily related to the CYP3A4 activity and none of the pyridine derivative metabolites of amlodipine have significant pharmacological activity [27]. However this metabolic route is not common, for example CYP-related metabolism of nonsteroidal antimineralocorticoid finerenone shows a similar oxidative pathway [28].…”

“…Our previous studies showed that the nature of the functional groups, the density of reactive groups and the hydrophobic/hydrophilic properties of catalyst carriers can be well-controlled by surface modifications by means binary and ternary mixtures of substituted organosilanes. The systematic combination of organosilanes provided improved immobilized biocatalysts built up from nanoparticles or nanoporous networks [16,[28][29][30][31]. MNPs with dual functions created by surface modification with binary mixtures of organosilanes (containing aminopropyl-trimethoxy silane:methyl-trimethoxysilane mixtures at molar ratios of 1:0, 1:1, 1:4, 1:16 and 0:1) had not previously been investigated yet for the immobilization of metalloporphyrins.…”