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.