Characterizing the Metabolic Fate and Pharmacokinetics of the RyR2 Inhibitor ent-Verticilide

ent-Verticilide is rapidly depleted in liver S9 fractions across mouse, rat, dog, and human, with in vitro half-lives of 2.1–5.3 min and NADPH dependence.

• Why it matters: Understanding its metabolic fate and pharmacokinetics is needed to clarify how hepatic oxidation shapes drug disposition and supports continued preclinical development for cardiac arrhythmias.
• What they did: Metabolic stability was tested in liver S9 fractions, followed by CYP reaction phenotyping in human microsomes and metabolite profiling in human and rat S9; pharmacokinetics were measured in rats after intravenous and oral dosing.
• The result: CYP3A predominates in metabolism, and eight putative metabolites were detected; in rats, systemic clearance was 29.6 mL/min/kg, steady-state volume 4.86 L/kg, terminal half-life 6.85 h, and oral bioavailability 10.5%.

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