Eicosanoid Metabolomic Profile of Remdesivir Treatment in Rat Plasma by High-Performance Liquid Chromatography Mass Spectrometry

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.

Integration Analysis of Pharmacokinetics and Metabolomics to Predict Metabolic Phenotype and Drug Exposure of Remdesivir

“…Both PCA and OPLS-DA were used to integrate and co-analyze all data to explore the longitudinal metabolic trajectory in all rats. Individuals were utilized as the grouping basis, and dots of the same color represented samples of one rat at different time points ( Du et al, 2021a ). From the results of Figure 2A , plasma samples of one rat were divided into tight clusters, which indicated that the longitudinal metabolic fingerprint of the same rat was relatively stable after remdesivir treatment.…”

“…Limited studies have been revealed for the metabolite changes among COVID-19 patient cohorts, such as cytosine and tryptophan–nicotinamide pathways ( Blasco et al, 2020 ), lipids ( Archambault et al, 2021 ), amino acids and fatty acids ( Shen et al, 2020 ), and eicosanoids ( Du et al, 2021a ). However, to the best of our knowledge, no comprehensive metabolic profiling literature studies were reported pertaining to remdesivir treatment both in vitro and in vivo .…”

Remdesivir does not affect mitochondrial DNA copy number or deletion mutation frequency in aged male rats

“…In contrast, when Bjork and Wallace [23] assessed the dose-dependent effect of remdesivir on mitochondrial DNA replication by exposing human hepatoma HepG2/C3A cells to increasing concentrations of remdesivir (0.1 to 10 µM) for 24 h and 48 h, they did not observe changes in mtDNA copy number. Given the pharmacokinetics of remdesivir in rats [33], our daily dose of 4.25 mg/kg of remdesivir is comparable to the human dose of 1.25mg/kg. The effects of remdesivir on the accumulation of mtDNA deletion mutations has received very little attention.…”

Remdesivir does not affect mitochondrial DNA copy number or deletion mutation frequency in aged male rats: A short report

“…In contrast, when Bjork and Wallace [ 26 ] assessed the dose-dependent effect of remdesivir on mitochondrial DNA replication by exposing human hepatoma HepG2/C3A cells to increasing concentrations of remdesivir (0.1 to 10 μM) for 24 h and 48 h, they did not observe changes in mtDNA copy number. Given the pharmacokinetics of remdesivir in rats [ 38 ], our daily dose of 4.25 mg/kg of remdesivir is comparable to the human dose of 1.25 mg/kg.…”

“…concentrations of remdesivir (0.1 to 10 μM) for 24 h and 48 h, they did not observe changes in mtDNA copy number. Given the pharmacokinetics of remdesivir in rats [38], our daily dose of 4.25 mg/kg of remdesivir is comparable to the human dose of 1.25 mg/kg.…”