Cardiac RyR2-blocking macrocycle is cleared fast by liver CYP3A oxidation and absorbs poorly by mouth
- The synthetic macrocyclic depsipeptide ent-verticilide blocks the cardiac ryanodine receptor RyR2 and is being explored for arrhythmia.
- Liver S9 fractions from four species depleted the compound quickly and in an NADPH-dependent way, with CYP3A the main enzyme family; metabolites were mostly oxidation products and looked alike in human and rat.
- In rats, clearance was fairly high, tissue distribution wide, and oral exposure low, giving a first DMPK baseline for further preclinical work.
💡 Points Based on the abstract
Fast CYP3A turnover plus poor oral exposure is the classic macrocycle story, so I'd ask first whether the RyR2 pharmacology justifies rescuing it. Efficacy in an arrhythmia model with IV or infusion dosing, and a free-concentration-versus-effect link, should come before any formulation work. Also test CYP3A inhibitor co-dosing in vitro to gauge how much interaction risk comes with it.
Characterizing the Metabolic Fate and Pharmacokinetics of the RyR2 Inhibitor ent-Verticilide ↗