Coggins Sally J, Kimble Benjamin, Malik Richard, Thompson Mary F, Norris Jacqueline M, Govendir Merran
Sydney School of Veterinary Science, The University of Sydney, Camperdown, Australia.
Centre for Veterinary Education, The University of Sydney, Camperdown, Australia.
Vet Q. 2024 Dec;44(1):1-9. doi: 10.1080/01652176.2024.2305731. Epub 2024 Jan 30.
Feline infectious peritonitis (FIP) is a potentially fatal coronavirus-driven disease of cats. Treatment with nucleoside analogue GS-441524 and or prodrug remdesivir (RDV) have produced remission in both experimentally induced and naturally occurring FIP, yet information regarding metabolism of RDV into GS-441524 in cats is scarce. This study assessed possible phase I metabolism of RDV in cats, utilising an feline microsome model with in vitro t and Cl calculated using the substrate depletion method. A previously validated high-performance liquid chromatography (HPLC) fluorescence method was utilised for detection and analysis of RDV and GS-441524. Qualitative yield of RDV and intermediate metabolite GS-441524 were determined following microsome incubation, then compared to whole blood and plasma incubations. microsome incubation resulted in rapid depletion of RDV, though it did not appear to resemble a conventional phase I-dependent reaction in cats, as it is in humans and dogs. Depletion of RDV into GS-441524 was demonstrated in whole blood , suggesting cats convert RDV to GS-441524, likely via blood esterases, as observed in mice and rats. RDV metabolism is unlikely to be impacted by impaired liver function in cats. Furthermore, as RDV depletes within minutes, whereas GS-441524 is very stable, whole blood or plasma GS-441524 concentrations, rather than plasma RDV concentrations, are more appropriate for therapeutic drug monitoring (TDM) in cats receiving RDV.
猫传染性腹膜炎（FIP）是一种由冠状病毒引起的、对猫有潜在致命性的疾病。用核苷类似物GS-441524和/或前药瑞德西韦（RDV）治疗已使实验诱导型和自然发生型FIP均出现缓解，但关于猫体内RDV代谢为GS-441524的信息却很少。本研究利用猫微粒体模型，采用底物消耗法计算体外t和Cl，评估了猫体内RDV可能的I相代谢。采用先前验证的高效液相色谱（HPLC）荧光法对RDV和GS-441524进行检测和分析。在微粒体孵育后测定RDV和中间代谢产物GS-441524的定性产率，然后与全血和血浆孵育结果进行比较。微粒体孵育导致RDV迅速消耗，不过在猫身上它似乎并不类似于人类和狗身上的传统I相依赖性反应。在全血中证实了RDV向GS-441524的消耗，这表明猫可能像在小鼠和大鼠中观察到的那样，通过血液酯酶将RDV转化为GS-441524。猫的RDV代谢不太可能受到肝功能受损的影响。此外，由于RDV在几分钟内就会耗尽，而GS-441524非常稳定，对于接受RDV治疗的猫，全血或血浆中GS-441524的浓度比血浆中RDV的浓度更适合用于治疗药物监测（TDM）。
