Potential Role of CYP3A4 in Determining In Vivo Exposure to Cannabidiol (CBD) and its Active Metabolite 7-OH-CBD: Evidence from an In Vitro Study.

Jaisupa N.; Birgersson S.; Ashton M. · European journal of drug metabolism and pharmacokinetics · 2026

**Background & Methods** This in vitro study investigated how combinations of commonly prescribed antiseizure medications (ASMs) influence the metabolism of cannabidiol (CBD) and its active metabolite 7-OH-CBD using human liver microsomes. CBD was incubated alone or with various ASM combinations (valproic acid, clobazam, stiripentol, topiramate, zonisamide, felbamate, perampanel, ethosuximide, rufinamide, lamotrigine, levetiracetam, and gabapentin), with quantification of metabolite concentrations via HPLC-MS/MS at eight time points. **Key Findings** • CYP3A4 inhibition emerged as the primary pathway affecting CBD exposure: ketoconazole (a potent CYP3A4 inhibitor) markedly reduced intrinsic clearance (CLint) of both CBD and 7-OH-CBD, while CYP2C19 and CYP2C9 inhibitors produced only minor reductions in CBD CLint. • Stiripentol demonstrated substantial CYP3A4-inhibitory potential, substantially decreasing CBD CLint and markedly reducing formation of both 7-OH-CBD and 7-COOH-CBD metabolites. • Co-incubation with four CYP3A4-substrate ASMs resulted in greater reduction in 7-OH-CBD CLint than in CBD CLint, suggesting differential metabolic effects on the parent drug versus active metabolite. **Dosage & Administration** Not reported. **Safety & Adverse Effects** Not reported. **Evidence Quality** This in vitro study represents preclinical evidence with significant limitations. The use of human liver microsomes does not fully replicate the complex hepatic metabolism occurring in vivo, including potential contributions from intestinal metabolism, enzyme induction, and systemic circulation dynamics. While the study provides mechanistic insight into CYP3A4's role in CBD metabolism, findings require confirmation through clinical pharmacokinetic studies to establish clinical relevance and predict actual drug-drug interactions in patients. The relevance of multiple ASM combinations tested remains uncertain regarding their true clinical prevalence and impact. No human studies were conducted, limiting direct applicability to clinical practice. These results suggest CYP3A4-mediated interactions warrant further investigation but should not guide clinical dosing decisions without supporting in vivo evidence.

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