Cannabidiol and Δ9-tetrahydrocannabinol induce drug-metabolizing enzymes, but not transporters, in human hepatocytes: Implications for predicting complex cannabinoid-drug interactions.

Abstract

Cannabidiol (CBD) or delta-9-tetrahydrocannabinol (THC) can inhibit multiple CYPs and UGTs in vivo and/or in vitro. CBD, but not THC, is also a time-dependent inhibitor of CYP3A, CYP1A2, and CYP2C19. We showed that a single 640 mg oral dose of CBD inhibits oral midazolam plasma clearance by 56%, whereas others found no interaction of chronic CBD with midazolam. These data can be explained if chronic CBD induces CYP3A enzymes. To investigate if CBD or THC induces CYP enzymes or transporters, we treated 4 lots of human hepatocytes for 72 hours with in vivo relevant concentrations of CBD (42 nM, 420 nM) or THC (250 nM, 700 nM). Then, mRNA expression and CYP activity were measured using quantitative polymerase chain reaction and liquid chromatography-tandem mass spectrometry, respectively. CYP3A4 mRNA was significantly induced to 7.3-, 11.1-, and 3.3-fold by CBD (420 nM) and 14.8-, 5.9-, and 3.1-fold by THC (700 nM) in 3 of the 4 lots. CYP3A activity was significantly induced 3.39- and 3.28-fold by low (42 nM) and 2.4- and 2.3-fold by high (420 nM) CBD concentrations, respectively, in 2 lots, and 2.3-fold by THC (700 nM) in 1 lot. Rifampin (10 μM) significantly induced CYP3A mRNA and activity across all lots. CBD (420 nM) significantly induced CYP1A2 and CYP2B6 mRNA (but not activity) in 2 lots. No significant induction of other CYPs, UGTs, or transporters was observed. Incorporation of CBD E_max and EC₅₀ of CYP3A4 mRNA induction (without scaling by rifampin mRNA induction) into a CBD physiologically-based pharmacokinetic model successfully captured the lack of the observed chronic CBD-midazolam drug interaction. SIGNIFICANCE STATEMENT: Time-dependent inhibition and induction of CYP3A enzymes by cannabidiol (CBD) is a plausible explanation for the significant CBD-midazolam pharmacokinetic interaction after single-dose CBD administration and the absence of such an interaction after multiple-dose CBD administration.