Effects of simulated exogenous and endogenous lipid microenvironments on cannabidiol disposition and cytochrome P450 2C19-mediated drug interactions: New mechanistic insights.

Nguyen A.; Rotich F.; Cech N.; Paine M. · Drug metabolism and disposition: the biological fate of chemicals · 2026

**Background & Methods** This in vitro study evaluated cannabidiol (CBD) effects on cytochrome P450 2C19 (CYP2C19) inhibition and drug metabolism using human liver microsomes (HLMs) under simulated lipid-rich conditions. The research examined CBD disposition in both normal hepatic tissue and tissue from patients with metabolic dysfunction-associated steatohepatitis (MASH) to determine how hepatic steatosis affects CBD-drug interactions. **Key Findings** - CYP2C19 demonstrated highest sensitivity to CBD inhibition with Ki values of 0.22 ± 0.03 μM (CBD in triglyceride mixture) and 0.16 ± 0.03 μM (purified CBD), with CYP2C19 activity reduced by 25-68% under simulated steatotic conditions depending on lipid type - Triglycerides and fatty acids enhanced CYP2C19 inhibitory effects of CBD by 1.3- to 3-fold, indicating lipid microenvironments substantially increase drug interaction potential - CBD intrinsic clearance via P450 pathways was significantly reduced in MASH-derived HLMs (0.33 ± 0.02 mL/min per mg) compared to normal HLMs (0.73 ± 0.03 mL/min per mg), suggesting impaired CBD metabolism in steatotic liver disease **Dosage & Administration** Not reported. **Safety & Adverse Effects** Not reported. **Evidence Quality** This in vitro mechanistic study provides foundational knowledge but has significant limitations for clinical translation. The research uses isolated liver microsome preparations rather than whole-animal or human studies, limiting ability to predict in vivo drug interactions. Findings are specific to CYP2C19 and may not generalize to other P450 enzymes or metabolic pathways. The study lacks clinical validation in actual patient populations with hepatic steatosis or MASH. Results suggest future clinical studies are needed to determine whether high-fat diets and steatotic liver disease clinically alter CBD disposition and drug interaction potential in humans. Evidence quality is Level 4 (in vitro mechanistic data).

More recent cannabis research