Abstract
Remdesivir, a nucleotide analog prodrug, has displayed pharmacological activity against SARS-CoV-2. Recently, eicosanoids are widely involved in regulating immunity and inflammation for COVID-19 patients. Rats were intravenously administered remdesivir at a dose of 5 mg/kg, and series of blood samples were collected before and after treatment. Targeted metabolomics regarding the eicosanoid profile were investigated and quantitated simultaneously using the previously reported reliable HPLC-MS/MS method. Additionally, interplay relationship between metabolomics and pharmacokinetic parameters was performed using the Pearson correlation analysis and PLS model. For the longitudinal metabolomics of remdesivir, metabolic profiles of the same rat were comparatively substantial at discrete sampling points. The metabolic fingerprints generated by individual discrepancy of rats were larger than metabolic disturbance caused by remdesivir. As for the transversal metabolomics, the prominent metabolic profile variation was observed between the baseline and treatment status. Except for TXB2, the inflammatory- and immunology-related eicosanoids of resolvin D2, 5-HEPE, 5-HETE, and DHA were significantly disturbed and reduced after single administration of remdesivir (p < 0.05, p < 0.001). Moreover, the metabolite of PGE2 correlated with GS-441524 (active metabolite of remdesivir) concentration and pharmacokinetic parameters of Cmax, AUC0-t, AUC0-infinity, and CL significantly. Eicosanoid metabolic profiles of remdesivir at both longitudinal and transversal levels were first revealed using the robust HPLC-MS/MS method. This initial observational eicosanoid metabolomics may lighten the therapy for fighting COVID-19 and further provide mechanistic insights of SARS-CoV-2 virus infection.
Highlights
Since December 2019, coronavirus disease 2019 (COVID-19) has strained the global healthcare system seriously (Zhu et al, 2020)
In view of the shortcomings described above, the purpose of the present study was originally proposed to longitudinally and transversally investigate the eicosanoid metabolic fingerprint induced by remdesivir treatment in rats
We provide the first deep interrogation of eicosanoid changes that benefit propitious understanding of how remdesivir interacted with small molecular metabolites
Summary
Since December 2019, coronavirus disease 2019 (COVID-19) has strained the global healthcare system seriously (Zhu et al, 2020). In the face of the current global pandemic posed by severe respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, there is an urgent necessitation to prompt a fervent search for effective therapy and to improve our knowledge of the metabolomic mechanism of this disease. A nucleotide analog prodrug, remdesivir, has broad-spectrum activity against a variety of viruses, such as Ebola, SARS-CoV-2, Middle East respiratory syndrome coronavirus (MERS-CoV), and COVID-19 in vitro and in vivo (Lamb, 2020). Remdesivir was authorized by the United States Food and Drug Administration for emergency use in November 2020 for treating patients with severe COVID-19. Clinical treatment of remdesivir has brought obvious benefit for patients with COVID-19 to some extent
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