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.
ABSTRACT
OBJECTIVE: To investigate associations between CYP3A4/5 and POR single nucleotide polymorphisms(SNPs)and tacrolimus dose-corrected concentrations(ρ0/D) in Chinese adult heart transplant recipients, providing individualized dose-adjustment for this population. METHODS: A total of 90 Chinese adult heart transplant recipients in the early stage were enrolled. CYP3A4*1G G>A(rs2242480) genotype was assessed by pyrophosphate sequencing. CYP3A5*3 A>G(rs776746) and POR*28 C>T(rs1057868) genotype were determined by Sanger sequencing. Tacrolimus trough concentration(ρ0) was evaluated by enzyme multiplied immunoassay technique(EMIT). Associations between genotypes and ρ0/D as well as time and dose to get the target range were completely analyzed. RESULTS: Allele frequencies of all the evaluated SNPs were consistent with Hardy-Weinberg equilibrium (P>0.05). The ρ0/D in CYP3A5*3/*3 carriers was considerably higher than that in *1/*1and *1/*3 carriers. Moreover, time to get the target range was significantly shortened and required dosage was also significantly reduced in CYP3A5*3/*3 carriers. The ρ0/D in CYP3A4*1/*1G carriers was remarkably decreased in comparison with the wild type. After stratification by CYP3A5*3 genotypes, no associations were observed between CYP3A4*1G and POR*28 genotypes and tacrolimus ρ0/D. POR*28 was not related to ρ0/D, but significantly prolonged time to target range. CONCLUSION: This study demonstrats that CYP3A4*1G and CYP3A5*3 polymorphisms are associated with tacrolimus concentrations, the test of these genotypes before transplantation may be useful for individualized medicine of tacrolimus.