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In Vitro Drug-Drug Interactions between Oxycodone and Commonly Co-Consumed Drugs in Rat and Human Liver Microsomes
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DOI：10.2174/0113892002446297260217075246.png)
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Abstract
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Introduction: Oxycodone is frequently co-consumed with xylazine, etizolam, diazepam, and methamphetamine during clinical and/or illicit use. Methods :We investigated oxycodone metabolism to its two main metabolites, the active oxymorphone and the inactive noroxycodone, and potential interactions with these four drugs, using rat (RLM) and human (HLM) liver microsomes. Results: In RLM, K-m values were similar for oxymorphone (115 mu M) and noroxycodone (128 mu M) formation, whereas in HLM, K-m values differed for oxymorphone (146 mu M) and noroxycodone (1.23 mM) formation. The CLint of oxycodone to noroxycodone was similar to 4-fold higher than oxycodone to oxymorphone, in both RLM and HLM. Xylazine inhibits (K-i) oxymorphone (1.9 mu M) and noroxycodone (4.4 mu M) formation in RLM more potently than in HLM (313 mu M and 247 mu M, respectively). Diazepam inhibits oxymorphone (5.0 mu M) and noroxycodone (5.6 mu M) formation in RLM more potently than in HLM (1.8 mM and 163 mu M, respectively). Etizolam inhibits oxymorphone (14.2 mu M) and noroxycodone (16.1 mu M) formation in RLM more potently than in HLM (550 mu M and 129 mu M, respectively). Methamphetamine is not a potent inhibitor of oxymorphone formation (487 mu M in RLM and 352 mu M 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. 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 oxycodone by CYP2D and CYP3A and the inhibition of metabolite formation in RLM versus HLM.
Keywords:
Oxycodone
drug metabolism
drug-drug interactions
CYP2D
CYP3A
inhibitors
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