BACKGROUND Researchers have long been interested in the potential drug-drug interactions (DDIs) between opioids and benzodiazepines. However, much remains unknown concerning the interactions between these two drug classes. The objective of this work is to study the mechanism underlying the DDIs between opioids and benzodiazepines from the perspective of their pharmacokinetic (PK) interactions. A PK interaction occurs when two drugs are metabolized by the same cytochrome P450 enzymes and is one of the most common reasons for DDIs. METHODS We quantitatively predicted the DDIs between three opioids (fentanyl, oxycodone and buprenorphine) and four benzodiazepines (alprazolam, diazepam, midazolam and triazolam) using a physiologically based pharmacokinetic (PBPK) modeling approach. A set of PBPK models was first constructed for these common opioids and benzodiazepines using SimCYP software, and the DDIs between them were then explored at various dosages. RESULTS Our simulation results suggested there were no PK interactions between normal doses of opioids and benzodiazepines; but weak interactions can be expected with the combination of opioids and overdosed benzodiazepines. Particular attention should be given to the combination of fentanyl and overdosed alprazolam since a PK interaction can be observed between them. CONCLUSION Our results appear to indicate that pharmacodynamics may play a more important role than PKs in causing DDIs between opioids and benzodiazepines. This study also demonstrated that molecular modeling can be a very useful tool to mitigate the problem of "missing metabolic reaction parameters" in PK modeling and simulation.

中文翻译：

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使用基于生理学的药代动力学（PBPK）建模和仿真预测阿片类药物和过量的苯二氮杂类药物之间的药物相互作用。

背景技术研究人员长期以来对阿片类药物和苯并二氮杂卓之间的潜在药物-药物相互作用（DDI）感兴趣。但是，关于这两种药物类别之间的相互作用，尚有许多未知数。这项工作的目的是从它们的药代动力学（PK）相互作用的角度研究阿片类药物和苯二氮卓类药物之间DDI的潜在机制。当两种药物被相同的细胞色素P450酶代谢时，就会发生PK相互作用，这是DDI的最常见原因之一。方法我们使用基于生理学的药代动力学（PBPK）建模方法，定量预测了三种阿片类药物（芬太尼，羟考酮和丁丙诺啡）与四种苯并二氮杂类药物（阿普唑仑，地西epa，咪达唑仑和三唑仑）之间的DDI。首先使用SimCYP软件为这些常见的阿片类药物和苯并二氮杂类建立了一组PBPK模型，然后以各种剂量探索了它们之间的DDI。结果我们的模拟结果表明，正常剂量的阿片类药物和苯并二氮杂s之间没有PK相互作用。但是阿片类药物和过量的苯二氮卓类药物的组合可能会产生弱相互作用。应特别注意芬太尼和过量的阿普唑仑的组合，因为在它们之间可以观察到PK相互作用。结论我们的结果似乎表明，药理动力学可能比PKs在引起阿片类药物和苯并二氮杂类药物之间的DDI方面起更重要的作用。这项研究还表明，分子建模可以作为缓解“