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 (CYP) 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 CYP inhibition potential and disposition of CBD were evaluated using human liver microsomes (HLMs). Consistent with clinical observations, CYP2C19 was the most sensitive to inhibition by CBD, as both a component of a mixture containing triglycerides (CBD m ) and in purified form (CBD p ), with K i values 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 (FAs) under simulated hepatic steatotic conditions. Triglycerides and FAs enhanced the CYP2C19 inhibitory effects of CBD p by 1.3- to 3-fold, respectively. The IC 50 for CBD p 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 CBD p via CYP and UDP-glucuronosyltransferase pathways in MASH HLMs (0.33 ± 0.02 and 0.15 ± 0.02 mL/min/mg, respectively) was lower compared to non-MASH HLMs (0.73 ± 0.03 and 0.18 ± 0.04 mL/min/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.