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

IF 2.3 4区医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current drug metabolism Pub Date : 2026-03-31 DOI:10.2174/0113892002446297260217075246

Weilong Gu, Rachel F Tyndale

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引用次数: 0

Abstract

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 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.

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羟考酮与常用药物在大鼠和人肝微粒体中的相互作用。

在临床和/或非法使用期间，羟可酮经常与噻嗪、乙唑仑、二西泮和甲基苯丙胺共同使用。方法：利用大鼠（RLM）和人（HLM）肝微粒体，研究氧可酮对其两种主要代谢物（活性氧-羟吗啡酮和非活性去甲氧可酮）的代谢，以及与这四种药物的潜在相互作用。结果：RLM中氧仿酮（115 μM）和去甲氧可酮（128 μM）形成的Km值相似，而HLM中氧仿酮（146 μM）和去甲氧可酮（1.23 mM）形成的Km值不同。在RLM和HLM中，羟考酮对去甲羟考酮的比值比羟考酮对羟吗啡酮的比值高约4倍。Xylazine对RLM中（Ki） ox-ymorphone （1.9 μM）和去氧可酮（4.4 μM）的抑制作用强于HLM（分别为313 μM和247 μM）。地西泮对RLM中氧吗啡酮（5.0 μM）和no-羟考酮（5.6 μM）的抑制作用强于HLM（分别为1.8 mM和163 μM）。乙替唑仑对RLM中氧吗啡酮（14.2 μM）和去甲氧可酮（16.1 μM）的抑制作用强于HLM（分别为550 μM和129 μM）。甲基苯丙胺不是氧吗啡酮形成（RLM中为487 μM， HLM中为352 μM）或去甲氧可酮形成（RLM中为5.8 mM， HLM中为2.7 mM）的有效抑制剂。RLM中对氧可酮和右美沙芬（一种探针底物）的抑制模式相似，证实了CYP2D和CYP3A分别介导氧可酮和去甲氧可酮的形成。讨论：总之，在大鼠中，氯嗪、地西泮和乙替唑仑可能引起与羟考酮的药代动力学药物-药物相互作用（pk - ddi），但在人类中不太可能发生这种作用。结论：在RLM和HLM中，CYP2D和CYP3A对氧酮的代谢以及对代谢物形成的抑制均存在明显的物种差异。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Current drug metabolism 医学-生化与分子生物学

CiteScore

4.30

自引率

4.30%

发文量

审稿时长

4-8 weeks

期刊介绍： Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism, pharmacokinetics, and drug disposition. The journal serves as an international forum for the publication of full-length/mini review, research articles and guest edited issues in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the most important developments. The journal covers the following general topic areas: pharmaceutics, pharmacokinetics, toxicology, and most importantly drug metabolism. More specifically, in vitro and in vivo drug metabolism of phase I and phase II enzymes or metabolic pathways; drug-drug interactions and enzyme kinetics; pharmacokinetics, pharmacokinetic-pharmacodynamic modeling, and toxicokinetics; interspecies differences in metabolism or pharmacokinetics, species scaling and extrapolations; drug transporters; target organ toxicity and interindividual variability in drug exposure-response; extrahepatic metabolism; bioactivation, reactive metabolites, and developments for the identification of drug metabolites. Preclinical and clinical reviews describing the drug metabolism and pharmacokinetics of marketed drugs or drug classes.