Revefenacin Absorption, Metabolism, and Excretion in Healthy Subjects and Pharmacological Activity of Its Major Metabolite

Bourdet, David L.; Yeola, Suresh; Hegde, Sharath S.; Colson, Philippe; Barnes, Chris; Borin, Marie T.

doi:10.1124/dmd.120.000103

Cited by 4 publications

(3 citation statements)

References 17 publications

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“…THRX-195518 is a molecule with a piperidine structure and a molecular weight of 598.73 g/mol (Figure 3). The literature reports that most PAM ligands exhibit a pyrimidine structure [42,43]. When examining drug-likeness and ADMET analysis for THRX-195518 and the other two mGlu2 activators in our study (LY 379268 and JNJ-46281222), it is observed that the molecules exhibit drug-likeness (Table 1).…”

Section: Discussionmentioning

confidence: 59%

“…By comparison, Revefenacin exhibited high affinity for all five muscarinic receptor subtypes. THRX-195518 has a tenfold lower binding affinity for the M3 receptor relative to Revefenacin, with receptor occupancy analysis suggesting a minimal contribution of THRX-195518 to systemic pharmacology relative to Revefenacin [42]. Muscarinic receptors belong to the GPCR family.…”

Section: Discussionmentioning

confidence: 99%

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Identification of the Candidate mGlu2 Allosteric Modulator THRX-195518 through In Silico Method and Evaluation of Its Neuroprotective Potential against Glutamate-Induced Neurotoxicity in SH-SY5Y Cell Line

Canbolat,

Kantarci-Carsibasi,

Isik

et al. 2024

CIMB

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Glutamate (Glu) toxicity has been an important research topic in toxicology and neuroscience studies. In vitro and in vivo studies have shown that Group II metabotropic Glu2 (mGlu2) activators have cell viability effects. This study aims to determine a candidate ligand with high mGlu2 allosteric region activity among cytotoxicity-safe molecules using the in silico positioning method and to evaluate its cell viability effect in vitro. We investigated the candidate molecule’s cell viability effect on the SH-SY5Y human neuroblastoma cell line by MTT analysis. In the study, LY 379268 (agonist) and JNJ-46281222 (positive allosteric modulator; PAM) were used as control reference molecules. Drug bank screening yielded THRX-195518 (docking score being −12.4 kcal/mol) as a potential novel drug candidate that has a high docking score and has not been mentioned in the literature so far. The orthosteric agonist LY 379268 exhibited a robust protective effect in our study. Additionally, our findings demonstrate that JNJ-46281222 and THRX-195518, identified as activating the mGlu2 allosteric region through in silico methods, preserve cell viability against Glu toxicity. Therefore, our study not only emphasizes the positive effects of this compound on cell viability against Glu toxicity but also sheds light on the potential of THRX-195518, acting as a mGlu2 PAM, based on in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) data, as a candidate drug molecule. These findings underscore the potential utility of THRX-195518 against both neurotoxicity and Central Nervous System (CNS) disorders, providing valuable insights.

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Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Identification of the Candidate mGlu2 Allosteric Modulator THRX-195518 through In Silico Method and Evaluation of Its Neuroprotective Potential against Glutamate-Induced Neurotoxicity in SH-SY5Y Cell Line

Canbolat,

Kantarci-Carsibasi,

Isik

et al. 2024

CIMB

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“…Metabolite pro les in pooled plasma and urine were determined using high-performance liquid chromatography (HPLC) with fraction collection by AMS (Pharmaron, Inc., Germantown, MD). Technical details for the AMS quantitation methods have been described previously [39]. Metabolite pro les in pooled homogenized feces were determined using HPLC with tandem mass spectrometry (LC-MS/MS) (Theravance Biopharma, South San Francisco).…”

Section: Methodsmentioning

confidence: 99%

The Metabolic Fate of Izencitinib, a Gut-selective Pan-JAK Inhibitor, in Humans. Identification of Unusual Fecal Metabolites and Implications for MIST Evaluation.

Yeola,

Badagnani,

Huang

et al. 2023

Preprint

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Izencitinib is a novel, orally administered pan-JAK inhibitor designed as a gut-selective therapy that was under development for the treatment of inflammatory bowel disease. The objectives of this study were to define the mass balance, routes and rates of excretion, and metabolic fate of izencitinib after oral administration of [14C]-izencitinib in humans. Six healthy adult male subjects were administered a single 100 mg (~ 300 mCi) oral dose of [14C]-izencitinib. Fecal excretion was the dominant route of elimination with > 90% of the administered dose recovered in the feces. Plasma concentrations of total radioactivity and izencitinib were low with the mean terminal half-life of total radioactivity (138 h) exceeding that of izencitinib (32.4 h). Izencitinib represented approximately 17% of the total circulating radioactivity, suggesting the presence of multiple circulating plasma metabolites. However, no metabolites exceeded 10% of total drug-related material in plasma. The major metabolites in feces, M18 and M9, were found to have unusual structures that reflected the presence of a nucleophilic carbon center in the naphthyridine ring of izencitinib. Proposed mechanisms for the formation of these metabolites involved oxidation and rearrangement (M18) and a one-carbon addition, potentially occurring through reaction with endogenous formaldehyde (M9). Given the gut-selective properties of izencitinib, it is proposed that these novel fecal metabolites are the most relevant for evaluating the impact of metabolism on the pharmacological and toxicological properties of izencitinib, and that the circulating plasma metabolite profile is of little consequence in the assessment of the safety characteristics of izencitinib metabolites.

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The metabolic fate of izencitinib, a gut-selective pan-JAK inhibitor, in humans. Identification of unusual fecal metabolites and implications for MIST evaluation

Yeola,

Badagnani,

Huang

et al. 2023

Med Chem Res

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Revefenacin Absorption, Metabolism, and Excretion in Healthy Subjects and Pharmacological Activity of Its Major Metabolite

Cited by 4 publications

References 17 publications

Identification of the Candidate mGlu2 Allosteric Modulator THRX-195518 through In Silico Method and Evaluation of Its Neuroprotective Potential against Glutamate-Induced Neurotoxicity in SH-SY5Y Cell Line

Identification of the Candidate mGlu2 Allosteric Modulator THRX-195518 through In Silico Method and Evaluation of Its Neuroprotective Potential against Glutamate-Induced Neurotoxicity in SH-SY5Y Cell Line

The Metabolic Fate of Izencitinib, a Gut-selective Pan-JAK Inhibitor, in Humans. Identification of Unusual Fecal Metabolites and Implications for MIST Evaluation.

The metabolic fate of izencitinib, a gut-selective pan-JAK inhibitor, in humans. Identification of unusual fecal metabolites and implications for MIST evaluation

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