{
  "abstract": "ent-Verticilide is a synthetic cyclic oligomeric depsipeptide that inhibits ryanodine receptor 2 (RyR2)-mediated calcium (Ca) leak and has demonstrated antiarrhythmic activity in mice. This study characterized the preclinical absorption, distribution, metabolism, and pharmacokinetic properties of ent-verticilide and investigated factors affecting its oral exposure. ent-Verticilide was stable in rat plasma and simulated gastric and intestinal fluids but exhibited extensive plasma protein binding (>94%) and low apparent permeability in Caco-2 cells, with no evidence of pronounced net efflux. In rat and human liver microsomes, ent-verticilide underwent rapid NADPH-dependent metabolism, with an in vitro half-life of 5.43 min and 4.35 min, respectively, and a predicted hepatic extraction ratio of 0.90 and 0.92, respectively. Following intravenous administration in rats, ent-verticilide exhibited a systemic clearance of 25.5 mL/min/kg and a large steady-state volume of distribution (4.72 L/kg). Absolute oral bioavailability was approximately 16%. Simultaneous portal and systemic sampling estimated intestinal availability (FaFg) at 0.25 and hepatic availability (Fh) at 0.64, suggesting that processes occurring before hepatic entry are a major limitation to oral exposure. Pretreatment with the CYP inhibitor 1-aminobenzotriazole increased portal and systemic exposure approximately 10.6- and 18.5-fold, respectively, and increased apparent Fh to approximately 1. Collectively, these findings identify limited intestinal availability and CYP-mediated presystemic metabolism as important determinants of ent-verticilide exposure and provide a framework for its continued development as an RyR2-targeted therapeutic.",
  "abstract_shown": true,
  "affiliations": [
    "Vanderbilt University Medical Center"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "name": "T. Q. Do"
    },
    {
      "name": "R. D. Crouch"
    },
    {
      "name": "K. Wu"
    },
    {
      "name": "M. P. Thorpe"
    },
    {
      "name": "A. N. Smith"
    },
    {
      "name": "J. N. Johnston"
    },
    {
      "name": "W. S. Akers"
    },
    {
      "affs": [
        0
      ],
      "name": "B. C. Knollmann"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/855k9a8yevnt0.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.26.761690",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.26.761690v1.full",
  "id": "855k9a8yevnt0",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.26.761690v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "pharmacology and toxicology"
    ],
    [
      "openalex",
      "3004|Pharmacogenetics and Drug Metabolism"
    ]
  ],
  "openalex": "W7223933594",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.26.761690v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-26",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/855k9a8yevnt0.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:29:51Z",
      "native_id": "10.64898/2026.10.26.761690",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.26.761690v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:pharmacology and toxicology",
      "subfield": "pharmacology-toxicology"
    }
  ],
  "title": "Characterization of the Preclinical in Vitro and in Vivo Pharmacokinetic Properties of the Cyclic Oligomeric Depsipeptide Ryanodine Receptor 2 Inhibitor ent-Verticilide",
  "title_text": "Characterization of the Preclinical in Vitro and in Vivo Pharmacokinetic Properties of the Cyclic Oligomeric Depsipeptide Ryanodine Receptor 2 Inhibitor ent-Verticilide",
  "type": "preprint",
  "updated_at": "2026-10-30T12:29:51Z",
  "url": "https://research.draconitic.com/paper/855k9a8yevnt0",
  "venue": "bioRxiv",
  "versions": []
}