Predicting in vivo cannabinoid-drug interactions mediated via inhibition of UDP-glucuronosyltransferases using in vitro studies and physiologically based pharmacokinetic modeling and simulations.

We previously reported the inhibitory potential of the most extensively studied cannabinoids, cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), along with their respective circulating metabolites, against a panel of cytochrome P450 (CYP) enzymes. In the current work, we characterized the inhibitory potential of these cannabinoids against a panel of recombinant human UDP-glucuronosyltransferases (UGTs). Upon screening CBD, THC, and their primary circulating metabolites (7-hydroxy CBD or 11-hydroxy THC) at 10 μM, cannabinoids likely to inhibit UGTs at pharmacologically relevant concentrations in vivo were characterized further. The unbound IC50 (IC50,u) for CBD, 7-hydroxy CBD, and THC, respectively, was 0.0015, 1.61, and 0.066 μM (UGT1A9); 0.015, 0.56, and 0.13 μM (UGT2B4); and 0.011, 1.28, and 0.071 μM (UGT2B7). The IC50,u for CBD against UGT1A4, 1A6, 2B10, and 2B15 was 1.22, 0.67, 0.49, and 0.56 μM, respectively. Using various established static models (using Cave,sys,u, Cmax,sys,u, or Cmax,hepatic inlet,u), the predicted magnitude of in vivo hepatic interaction (ratio of the area under the plasma concentration vs. time curve [area under the curve] of the object drug in the presence to absence of cannabinoid) between CBD (700 mg bid oral) and a putative object drug that is extensively metabolized (fm = 0.75) by UGT1A9, 2B4, and 2B7 ranged from 2.2-3.9, 1.3-3.0, and 1.3-3.2, respectively. The physiologically based pharmacokinetic model predicted increase in the area under the curve of dapagliflozin (UGT1A9 substrate; fm = 0.80) and zidovudine (UGT2B7 substrate; fm = 0.70) was 126% and 30%, respectively, upon multiple oral dosing of CBD (700 mg bid). In vivo drug interaction studies using UGT1A9, 2B4, and 2B7 probe drugs are necessary to verify our pharmacokinetic CBD-drug interaction predictions. SIGNIFICANCE STATEMENT: This study represents a comprehensive determination of the potency (IC50,u) of cannabidiol, Δ9-tetrahydrocannabinol, and their metabolites as inhibitors of recombinant human UDP-glucuronosyltransferases. Among these cannabinoids, cannabidiol was the most potent inhibitor of UGT1A9, 2B4, and 2B7. Using static and physiologically based pharmacokinetic models, we predicted weak to moderate pharmacokinetic interactions between chronic cannabidiol (but not Δ9-tetrahydrocannabinol) administration and object drugs predominantly metabolized by UGT1A9, 2B4, or 2B7.