Dataset Information

Activation of PXR causes drug interactions with Paxlovid in transgenic mice.

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.

SUBMITTER: Lei S

PROVIDER: S-EPMC10638548 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Activation of PXR causes drug interactions with Paxlovid in transgenic mice.

Lei Saifei S Guo Alice A Lu Jie J Qi Qian Q Devanathan Aaron S AS Zhu Junjie J Ma Xiaochao X

Acta pharmaceutica Sinica. B 20230807 11

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 NM ...[more]

PMID: 37969744

Similar Datasets

Project description:IntroductionOral administration of ritonavir-boosted nirmatrelvir (Paxlovid) was found to be promising in the treatment of coronavirus disease 2019. The active antiviral component nirmatrelvir in Paxlovid is co-formulated with ritonavir, a strong cytochrome P450 (CYP) 3A4 inhibitor. Many oral targeted therapies indicated for lung cancer are known substrates of CYP 3A4, and concurrent use with Paxlovid may lead to potential drug-drug interaction (DDI). The purpose of this review is to evaluate the potential DDI between targeted therapies and supportive care for lung cancer and ritonavir-boosted nirmatrelvir.MethodsDrug database search in PubMed and the Food and Drug Administration was conducted to identify pharmacokinetic data on oral tyrosine kinase inhibitors (TKIs) used in NSCLC, both Food and Drug Administration approved and those in development. Metabolism pathways for various TKIs are extracted, and the impact of TKI area under the curves and maximum concentration by strong CYP 3A4 inducers and inhibitors is summarized. The most common toxicities and supportive care medications for the TKI were identified.ResultsAmong EGFR and exon 20 insertion inhibitors, afatinib is least likely to be affected by CYP 3A4, followed by dacomitinib and osimertinib. Among ALK inhibitors, alectinib is the least susceptible to CYP 3A4. ROS1 inhibitors are affected by CYP 3A4 inhibition with the exception of crizotinib. Among MET inhibitors, capmatinib is substantially affected by CYP 3A4 inhibition. Drug exposure of RET inhibitors is expected to increase with CYP 3A4 inhibition, with selpercatinib being the least affected. Certain supportive care medications for lung cancer TKI may have relevant DDIs.ConclusionsThe clinical impact of the DDI between lung cancer TKI and ritonavir-boosted nirmatrelvir varies largely on the basis of the susceptibility of CYP 3A4 inhibition caused by the antiviral. Close monitoring and medication adjustments (i.e., dose changes or alternative coronavirus disease 2019 therapy) can be used to overcome DDI to ensure patient safety.

Project description:BackgroundExposure to plastic-associated endocrine disrupting chemicals (EDCs) has been associated with an increased risk of cardiovascular disease (CVD) in humans. However, the underlying mechanisms for this association are unclear. Many EDCs have been shown to function as ligands of the nuclear receptor pregnane X receptor (PXR), which functions as xenobiotic sensor but also has pro-atherogenic effects in vivo.ObjectiveWe sought to investigate the contribution of PXR to the adverse effects dicyclohexyl phthalate (DCHP), a widely used phthalate plasticizer, on lipid homeostasis and CVD risk factors.MethodsCell-based assays, primary organoid cultures, and PXR conditional knockout and PXR-humanized mouse models were used to investigate the impact of DCHP exposure on PXR activation and lipid homeostasis in vitro and in vivo. Targeted lipidomics were performed to measure circulating ceramides, novel predictors for CVD.ResultsDCHP was identified as a potent PXR-selective agonist that led to higher plasma cholesterol levels in wild-type mice. DCHP was then demonstrated to activate intestinal PXR to elicit hyperlipidemia by using tissue-specific PXR-deficient mice. Interestingly, DCHP exposure also led to higher circulating ceramides in a PXR-dependent manner. DCHP-mediated PXR activation stimulated the expression of intestinal genes mediating lipogenesis and ceramide synthesis. Given that PXR exhibits considerable species-specific differences in receptor pharmacology, PXR-humanized mice were also used to replicate these findings.DiscussionAlthough the adverse health effects of several well-known phthalates have attracted considerable attention, little is known about the potential impact of DCHP on human health. Our studies demonstrate that DCHP activated PXR to induce hypercholesterolemia and ceramide production in mice. These results indicate a potentially important role of PXR in contributing to the deleterious effects of plastic-associated EDCs on cardiovascular health in humans. Testing PXR activation should be considered for risk assessment of phthalates and other EDCs. https://doi.org/10.1289/EHP9262.

Dataset Information

Activation of PXR causes drug interactions with Paxlovid in transgenic mice.

Publications

Activation of PXR causes drug interactions with Paxlovid in transgenic mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets