{
  "abstract": "{Delta}-tetrahydrocannabinol ({Delta}8-THC) is a pharmacologically active isomer of {Delta}9-THC, the main psychoactive component of cannabis. {Delta}8-THC use has increased rapidly, but the metabolism of {Delta}8-THC has been incompletely characterized. This study identified metabolites of {Delta}8-THC formed by cytochrome P450 (CYP) enzymes in human liver microsomes (HLM), assigned the main CYPs responsible for the metabolic pathways, and evaluated the impact of genetic polymorphisms on {Delta}8-THC metabolism in vitro. Five monohydroxylated {Delta}8-THC metabolites, identified as 11-OH-{Delta}8-THC, two aliphatic side-chain hydroxylated products (M1, M2), and two ring hydroxylated products (M3, M4) were detected in HLM. 11-OH-{Delta}8-THC was the most abundant metabolite. Unbound binding constants for metabolite formation in HLM ranged from 3.6 nM to >121 nM, suggesting multiple enzymes contribute to {Delta}8-THC metabolism. The contributing enzymes were identified using recombinant CYPs, inhibition studies, and correlation analyses. 11-OH-{Delta}8-THC was predominantly formed by CYP2C9 with a minor contribution from CYP2C19. CYP2C9 genotype-based activity scores across donors correlated with 11-OH-{Delta}8-THC formation (p = 0.0315). An 80% decrease in 11-OH-{Delta}8-THC formation clearance was predicted in CYP2C9*3/*3 carriers. The ring-hydroxylated M3 and M4 were mainly formed by CYP3A. CYP2D6, CYP1A2, and CYP3A4 activities were associated with formation of the pentyl side-chain oxidized metabolites M1 and M2. Although C11 hydroxylation appeared more important metabolic pathway for {Delta}8-THC than for {Delta}9-THC, the catalytic efficiency of CYP2C9 towards {Delta}8-THC was lower than towards {Delta}9-THC. In the presence of CYP2C9 inhibitors or genetic polymorphisms, {Delta}8-THC clearance is likely mediated by CYP3A4 and CYP2C19. This study shows that 11-OH-{Delta}8-THC, a psychoactive metabolite, is the primary oxidation product of {Delta}8-THC in HLM and that CYP2C9 predominantly catalyzes its formation. This work expands the limited literature on {Delta}8-THC metabolism, and shows that reduced-function CYP2C9 variants substantially impair formation of 11-OH-{Delta}8-THC. The characterization of {Delta}8-THC metabolism in HLM provides the foundation for risk assessment of drug-drug interactions and establishes the metabolic profile of {Delta}8-THC in the human liver.",
  "abstract_shown": true,
  "affiliations": [
    "University of Washington"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "name": "K. Simon"
    },
    {
      "name": "Y. W. Wen"
    },
    {
      "name": "Y. E. Dong"
    },
    {
      "name": "A. Authement"
    },
    {
      "name": "J. Chen"
    },
    {
      "name": "K. E. Thummel"
    },
    {
      "affs": [
        0
      ],
      "name": "N. Isoherranen"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/3fpez7c3yzfa2.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.12.758575",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.12.758575v1.full",
  "id": "3fpez7c3yzfa2",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.12.758575v1",
  "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": "W7222931678",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.12.758575v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-12",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/3fpez7c3yzfa2.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:28:36Z",
      "native_id": "10.64898/2026.10.12.758575",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.12.758575v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:pharmacology and toxicology",
      "subfield": "pharmacology-toxicology"
    }
  ],
  "title": "Characterization of Cytochrome P450-Mediated Metabolism of Δ8-tetrahydrocannabinol in vitro",
  "title_text": "Characterization of Cytochrome P450-Mediated Metabolism of Δ8-tetrahydrocannabinol in vitro",
  "type": "preprint",
  "updated_at": "2026-10-30T12:28:36Z",
  "url": "https://research.draconitic.com/paper/3fpez7c3yzfa2",
  "venue": "bioRxiv",
  "versions": []
}