Characterization of the Preclinical in Vitro and in Vivo Pharmacokinetic Properties of the Cyclic Oligomeric Depsipeptide Ryanodine Receptor 2 Inhibitor ent-Verticilide

ent-Verticilide shows limited oral exposure in rats, with absolute oral bioavailability of ~16% driven by low intestinal availability (FaFg 0.25) and CYP-mediated presystemic metabolism.

• Why it matters: Oral dosing is constrained by absorption and presystemic metabolism, yet ent-verticilide’s pharmacokinetic determinants were not defined for guiding RyR2-targeted therapeutic development.
• What they did: The study assessed stability in rat plasma and simulated gastric/intestinal fluids, measured Caco-2 permeability and plasma protein binding (>94%), characterized NADPH-dependent microsomal metabolism (half-life 5.43 min in rat, 4.35 min in human), and performed IV and oral rat PK with portal/systemic sampling.
• The result: IV dosing in rats yielded clearance of 25.5 mL/min/kg and steady-state volume of distribution 4.72 L/kg; CYP inhibition with 1-aminobenzotriazole increased portal and systemic exposure ~10.6- and 18.5-fold and raised apparent hepatic availability (Fh) to ~1.