Inhibitory Effects of Major Cannabinoids and their Metabolites on Oxazepam Metabolism

Cannabis and cannabis-derived products are increasingly used for recreational and medical purposes including anxiety and epilepsy and are often concurrently used with other types of conventional medications. The concomitant use of cannabis with other therapeutic drugs has been shown to increase the likelihood of deleterious drug-drug interactions. Oxazepam is a well-known benzodiazepine used in clinical practice as an anxiolytic, sedative, and anticonvulsant agent. Oxazepam is a racemic mixture of the S-and R-enantiomers and is primarily metabolized via glucuronidation in an enantiomeric-specific manner, where S-oxazepam is mainly glucuronidated by UDP-glucuronosyltransferase (UGT) 2B15 and R-oxazepam is glucuronidated primarily by UGT1A9 and UGT2B7. Recent comprehensive in vitrostudies using probe substrates have shown that the major cannabinoids Δ⁹– tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN) can inhibit several of the primary hepatic and renal UGT enzymes. The objective of the present study was to evaluate the potential inhibitory effect of cannabinoids and their major circulating metabolites, 11-hydroxy-Δ⁹-tetrahydrocannabinol (11-OH-THC), 11- nor-9-carboxy-Δ⁹-tetrahydrocannabinol (11-COOH-THC), and 11-nor-Δ⁹-tetrahydrocannabinol-carboxylic acid glucuronide (THC-COOH-Gluc) on the UGT enzymes involved in R,S-oxazepam metabolism. We hypothesize that major cannabinoids and their metabolites will inhibit R,S-oxazepam metabolism, leading to decreased clearance. To investigate potential drug-drug interactions, cannabinoids and their major plasma metabolites were screened as inhibitors of R- and S-oxazepam glucuronidation in human liver microsomes (HLM). In vitro inhibition screening assays with 10 μM or 100 μM of CBD and 11-OH-THC inhibited both R- and S-oxazepam glucuronidation in HLM by up to 90%. The IC₅₀ values 11-OH-THC and CBD inhibition of R-oxazepam glucuronidation were 10.0 ± 7.8 μM and 7.0 ± 4.2 μM, respectively, in HLM; the respective IC₅₀ values for the inhibition of S-oxazepam glucuronidation by 11-OH-THC and CBD were 15.0 ± 6.4 μM and 52.2 ± 22.6 μM in HLM. These data indicate that co-administration of oxazepam with cannabis may result in inhibition of oxazepam clearance, suggesting a strong potential for drug-drug interactions in vivo.