In Vitro Drug–Drug Interactions between Oxycodone and Commonly Co-Consumed Drugs in Rat and Human Liver Microsomes

Introduction: Oxycodone is frequently co-consumed with xylazine, etizolam, di-azepam, and methamphetamine during clinical and/or illicit use. Methods: We investigated oxycodone metabolism to its two main metabolites, the active ox-ymorphone and the inactive noroxycodone, and potential interactions with these four drugs, using rat (RLM) and human (HLM) liver microsomes. results: In RLM, Km values were similar for oxymorphone (115 μM) and noroxycodone (128 μM) formation, whereas in HLM Km values differed for oxymorphone (146 μM) and noroxycodone (1.23 mM) formation. The CLint of oxycodone to noroxycodone were ~4-fold higher than oxycodone to oxymorphone, in both RLM and HLM. Xylazine inhibits (Ki) oxymorphone (1.9 μM) and noroxycodone (4.4 μM) formation in RLM more potently than in HLM (313 μM and 247 μM, respectively). Diazepam inhibits oxymorphone (5.0 μM) and noroxycodone (5.6 μM) formation in RLM more potently than in HLM (1.8 mM and 163 μM, respectively). Etizolam inhibits oxymorphone (14.2 μM) and noroxycodone (16.1 μM) formation in RLM more potently than in HLM (550 μM and 129 μM, respectively). Methamphetamine is not a potent inhibitor of oxymorphone formation (487 μM in RLM and 352 μM in HLM) or noroxycodone formation (5.8 mM in RLM and 2.7 mM in HLM). Similar inhibition patterns in RLM for both oxycodone and dextromethorphan, a probe substrate, confirmed that CYP2D and CYP3A mediate oxymorphone and noroxycodone formation respectively. Results: In RLM, Km values were similar for oxymorphone (115 μM) and noroxycodone (128 μM) formation, whereas in HLM, Km values differed for oxymorphone (146 μM) and noroxycodone (1.23 mM) formation. The CLint of oxycodone to noroxycodone was ~4-fold higher than oxycodone to oxymorphone, in both RLM and HLM. Xylazine inhibits (Ki) ox-ymorphone (1.9 μM) and noroxycodone (4.4 μM) formation in RLM more potently than in HLM (313 μM and 247 μM, respectively). Diazepam inhibits oxymorphone (5.0 μM) and no-roxycodone (5.6 μM) formation in RLM more potently than in HLM (1.8 mM and 163 μM, respectively). Etizolam inhibits oxymorphone (14.2 μM) and noroxycodone (16.1 μM) for-mation in RLM more potently than in HLM (550 μM and 129 μM, respectively). Metham-phetamine is not a potent inhibitor of oxymorphone formation (487 μM in RLM and 352 μM in HLM) or noroxycodone formation (5.8 mM in RLM and 2.7 mM in HLM). Similar inhi-bition patterns in RLM for both oxycodone and dextromethorphan, a probe substrate, con-firmed that CYP2D and CYP3A mediate oxymorphone and noroxycodone formation, respec-tively. Discussion: In summary, xylazine, diazepam, and etizolam may cause pharmacokinetic drug-drug interactions (PK-DDIs) with oxycodone in rats but are unlikely to do so in humans. Conclusion: Substantial species differences were observed in both the metabolism of oxyco-done by CYP2D and CYP3A and the inhibition of metabolite formation in RLM versus HLM.