UGT2B7-mediated drug–drug interaction between cannabinoids and hydromorphone

Hydromorphone is a highly potent opioid used to treat severe chronic pain. It is metabolized primarily by UDP-glucuronosyltransferase (UGT)2B7 to form the inactive hydromorphone-3-glucuronide. Given that previous studies have shown that the major cannabinoids, Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD), inhibit several UGT enzymes, the objective of the present study was to determine the inhibitory potential of major cannabinoids and their metabolites on UGT-mediated hydromorphone metabolism. To evaluate the potential for cannabis-induced drug interactions, cannabinoids and their metabolites were screened as potential inhibitors against hydromorphone glucuronidation in pooled human liver microsomes and microsomes from cells overexpressing recombinant UGT2B7. IC₅₀ values were determined for cannabinoids that inhibited hydromorphone glucuronidation by 50% and K_i values for those that exhibited an IC₅₀ < 100 μM in human liver microsomes. Potent inhibition of hydromorphone metabolism was observed for THC, 11-hydroxy (OH)-THC, CBD, and 7-OH-CBD, with K_i values ranging from 0.068 to 1.01 μM after correction for nonspecific cannabinoid binding. Differences in inhibition were observed for the UGT2B7^268Tyr variant compared with the wildtype UGTB7^268His isoform for several cannabinoids. Static modeling indicated that THC, 11-OH-THC, CBD, and 7-OH-CBD would result in drug interactions in vivo after inhalation and oral consumption of THC and CBD (>1.25-fold increase in hydromorphone exposure), with physiologically based pharmacokinetic predictive models indicating that CBD would cause a 20%-30% increase in hydromorphone exposure in healthy and cirrhotic individuals. These data suggest that major cannabinoids such as CBD will cause moderate drug-drug interactions with hydromorphone in humans. SIGNIFICANCE STATEMENT: This study indicates that major cannabinoids and their metabolites found in the plasma of cannabis users inhibit UGT2B7-mediated hydromorphone metabolism in vitro. It further demonstrates the potential for in vivo inhibition of hydromorphone metabolism by cannabinoids and their metabolites, indicating the potential for drug-drug interactions upon concomitant use of hydromorphone and cannabis or hydromorphone together with individual cannabinoids like Δ⁹-tetrahydrocannabinol and cannabidiol.