RyR2 inhibitor ent-verticilide: modest oral exposure limited by gut absorption and CYP first pass
- The ADME profile of the RyR2-selective depsipeptide was worked up in rats and human liver microsomes: highly plasma-protein bound, rapidly metabolized, with oral bioavailability in the low range.
- Limited intestinal availability and CYP-mediated first-pass metabolism were identified as the main barriers to oral exposure.
💡 Points Based on the abstract
A cyclic depsipeptide that is both permeability-limited and CYP-cleared is a hard combination to fix, and this is the data that tells the team where to push. With high protein binding, the unbound exposure at an efficacious dose is the number I'd want next, along with which CYPs are involved, since that decides the interaction risk in arrhythmia patients who are often on several drugs.