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

Cannabidiol (CBD) is an in vitro inhibitor of multiple cytochrome P450 (P450) enzymes, which has been confirmed in healthy adults. Whether these observations translate to different patient populations, including those with hepatic steatosis, is not known. Accordingly, the effects of simulated exogenous and endogenous lipid microenvironments on the P450 inhibition potential and disposition of CBD were evaluated using human liver microsomes (HLMs). Consistent with clinical observations, CYP2C19 was most sensitive to inhibition by CBD as both a component of a mixture containing triglycerides (CBDm) and in purified form (CBDp), with a Ki of 0.22 ± 0.03 and 0.16 ± 0.03 μM, respectively. CYP2C19 activity (S-mephenytoin 4'-hydroxylation) decreased by 25% ± 3.5% and 68% ± 0.4%, respectively, upon exposure to triglycerides and fatty acids under simulated hepatic steatotic conditions. Triglycerides and fatty acids enhanced the CYP2C19 inhibitory effects of CBDp by 1.3- to 3-fold, respectively. The IC50 for CBDp against CYP2C19 activity in HLMs from donors with and without metabolic dysfunction-associated steatohepatitis (MASH) was 1.28 ± 0.25 and 1.12 ± 0.23 μM, respectively. Intrinsic clearance of CBDp via P450 and UDP-glucuronosyltransferase pathways in MASH HLMs (0.33 ± 0.02 and 0.15 ± 0.02 mL/min per mg, respectively) was lower compared with non-MASH HLMs (0.73 ± 0.03 and 0.18 ± 0.04 mL/min per mg, respectively). Results from this collection of in vitro experiments provide foundational knowledge that informs future research regarding the effects of a high-fat diet and steatotic liver disease on CBD disposition and CYP2C19-mediated drug interactions. SIGNIFICANCE STATEMENT: Exposure of human liver microsomes to simulated exogenous and endogenous lipid microenvironments provided new mechanistic insight into the direct effects of triglycerides and fatty acids on cannabidiol disposition and CYP2C19-mediated cannabidiol-drug interactions. Modified in vitro hepatic models, including human liver microsomes and human hepatocytes, under hepatic steatotic and metabolic dysfunction-associated steatohepatitis conditions could be applied to future studies aimed at evaluating the disposition and drug interaction potential of other drugs in these specific populations.