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In Vitro Drug-Drug Interactions between Oxycodone and Commonly Co-Consumed Drugs in Rat and Human Liver Microsomes
Weilong Gu1, Rachel F Tyndale1,2,3
1Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
Current Drug Metabolism
|April 17, 2026
Summary
Oxycodone metabolism differs significantly between rats and humans. Co-administered drugs like xylazine, diazepam, and etizolam inhibit oxycodone metabolism in rats but not humans, indicating potential species-specific drug interactions.
Area of Science:
- Pharmacology
- Drug Metabolism
- Toxicology
Background:
- Oxycodone is frequently co-administered with other substances, including xylazine, etizolam, diazepam, and methamphetamine.
- Understanding potential drug-drug interactions is crucial for both clinical and illicit use scenarios.
Purpose of the Study:
- To investigate the metabolism of oxycodone into its active (oxymorphone) and inactive (noroxycodone) metabolites.
- To assess the potential for pharmacokinetic drug-drug interactions (PK-DDIs) between oxycodone and four co-administered drugs using rat and human liver microsomes.
Main Methods:
- Utilized rat liver microsomes (RLM) and human liver microsomes (HLM) to study oxycodone metabolism.
- Quantified the formation of oxymorphone and noroxycodone and evaluated the inhibitory effects of xylazine, etizolam, diazepam, and methamphetamine.
Main Results:
- CYP2D and CYP3A were identified as the primary enzymes responsible for oxymorphone and noroxycodone formation, respectively.
- Xylazine, diazepam, and etizolam demonstrated potent inhibition of oxycodone metabolite formation in RLM, but significantly weaker inhibition in HLM.
- Methamphetamine showed minimal inhibitory effects on oxycodone metabolism in both RLM and HLM.
Conclusions:
- Significant species differences exist in oxycodone metabolism and the inhibitory potential of co-administered drugs between rats and humans.
- Xylazine, diazepam, and etizolam are unlikely to cause clinically significant PK-DDIs with oxycodone in humans due to species-specific metabolic pathways.
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