Activation of PXR causes drug interactions with Paxlovid in transgenic mice  

作　　者：Saifei Lei Alice Guo Jie Lu Qian Qi Aaron S.Devanathan Junjie Zhu Xiaochao Ma 

机构地区：[1]Center for Pharmacogenetics,Department of Pharmaceutical Sciences,School of Pharmacy,University of Pittsburgh,Pittsburgh,PA 15261,USA [2]School of Nursing,University of Pennsylvania,Philadelphia,PA 19104,USA [3]Department of Pharmacy and Therapeutics,School of Pharmacy,University of Pittsburgh,Pittsburgh,PA 15261,USA

出　　处：《Acta Pharmaceutica Sinica B》2023年第11期4502-4510,共9页药学学报（英文版）

基　　金：supported in part by the National Center for Complementary and Integrative Health (R21AT011088,USA);the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK126875,USA);the National Institute of Allergy and Infectious Diseases (R01AI131983,USA)。

摘　　要：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.

关 键 词：Paxlovid Nirmatrelvir Ritonavir Pregnane X receptor CYP3A4/5 RIFAMPICIN RHYNCHOPHYLLINE Drug/herb-drug interactions 

分 类 号：R96[医药卫生—药理学]