PDF(Pubmed)
Abstract：
Paxlovid is a nirmatrelvir (NMV) and ritonavir (RTV) co-packaged medication used for the treatment of coronavirus disease 2019 (COVID-19). The active component of Paxlovid is NMV and RTV is a pharmacokinetic booster. Our work aimed to investigate the drug/herb-drug interactions associated with Paxlovid and provide mechanism-based guidance for the clinical use of Paxlovid. By using recombinant human cytochrome P450s (CYPs), we confirmed that CYP3A4 and 3A5 are the major enzymes responsible for NMV metabolism. The role of CYP3A in Paxlovid metabolism were further verified in Cyp3a-null mice, which showed that the deficiency of CYP3A significantly suppressed the metabolism of NMV and RTV. Pregnane X receptor (PXR) is a ligand-dependent transcription factor that upregulates CYP3A4/5 expression. We next explored the impact of drug- and herb-mediated PXR activation on Paxlovid metabolism in a transgenic mouse model expressing human PXR and CYP3A4/5. We found that PXR activation increased CYP3A4/5 expression, accelerated NMV metabolism, and reduced the systemic exposure of NMV. In summary, our work demonstrated that PXR activation can cause drug interactions with Paxlovid, suggesting that PXR-activating drugs and herbs should be used cautiously in COVID-19 patients receiving Paxlovid.
摘要：
Paxlovid是尼马特雷韦（NMV）和利托那韦（RTV）共同包装的药物，用于治疗2019年冠状病毒病（COVID-19）。Paxlovid的活性成分是NMV，RTV是药代动力学增强剂。我们的工作旨在研究与Paxlovid相关的药物/草药-药物相互作用，并为Paxlovid的临床使用提供基于机制的指导。通过使用重组人细胞色素P450（CYPs），我们证实CYP3A4和3A5是负责NMV代谢的主要酶。在Cyp3a-null小鼠中进一步验证了CYP3A在Paxlovid代谢中的作用，表明CYP3A的缺乏显著抑制了NMV和RTV的代谢。孕烷X受体(PXR)是上调CYP3A4/5表达的配体依赖性转录因子。接下来，我们在表达人PXR和CYP3A4/5的转基因小鼠模型中探索了药物和草药介导的PXR激活对Paxlovid代谢的影响。我们发现PXR激活增加CYP3A4/5的表达，加速NMV代谢，减少了NMV的全身暴露。总之,我们的工作表明，PXR激活可以引起与Paxlovid的药物相互作用，提示在接受Paxlovid的COVID-19患者中，应谨慎使用PXR激活药物和草药。
