Inhibition of Morphine Metabolism by Major Cannabinoids and their Metabolites

Abstract

Opioids including morphine are mu‐opioid receptor (MOR) agonists that suppress excitatory neurotransmitter release, hyperpolarize neuronal cells, and decrease overall excitability, resulting in the desired analgesic effect. As a result of their over‐prescription, the still‐growing opioid epidemic has devastated many communities, with many individuals often using them in combination with other drugs including cannabis. Morphine is primarily metabolized by the phase II enzyme UDP‐glucuronosyltransferase (UGT) 2B7 to an inactive metabolite, morphine‐3‐glucuronide (M3G), and an active metabolite, morphine‐6‐glucuronide (M6G), both of which are extensively excreted into the urine. Previous studies in our lab have shown that major cannabis constituents including Δ9‐tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN) inhibit several major UGT enzymes. To examine whether cannabinoids or their major metabolites inhibit morphine glucuronidation by UGT2B7, screening assays were performed in pooled human liver microsomes (HLM) with the major cannabinoids and THC 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‐COO‐Gluc). IC50 values were then determined for those cannabinoids that exhibited at least 50% inhibition at 100 µM final concentration. THC, 11‐OH‐THC, THC‐COO‐Gluc, and CBD all exhibited greater than 50% inhibition of both M3G and M6G formation at either 10 or 100 µM. The IC50 values for THC, 11‐OH‐THC, THC‐COO‐Gluc, and CBD against M3G formation were determined to be 27 ± 9.97 µM, 5.97 ± 2.31 µM, 15.58 ± 12.28 µM, and 15.66 ± 19.98 µM, respectively. The IC50 values for THC, 11‐OH‐THC, THC‐COO‐Gluc, and CBD against M6G formation were 14.49 ± 4.03 µM, 6.26 ± 0.76 µM, 13.22 ± 5.28 µM, and 8.12 ± 9.64 µM, respectively. To confirm results from these inhibition screenings, M3G and M6G formation were further examined using microsomal fractions from HEK293 cells overexpressing recombinant UGT2B7. THC, 11‐OH‐THC, THC‐COO‐Gluc, and CBD all exhibited >50% inhibition of both M3G and M6G formation at either 10 or 100 µM in the recombinant enzyme system. These data suggest that several cannabinoids and their metabolites inhibit morphine metabolism, and that the co‐use of these agents may lead to adverse drug events in humans.