Assessing in vitro stability of remdesivir (GS-5734) and conversion to GS-441524 in feline plasma and whole blood.

IF 7.9 2区 农林科学 Q1 VETERINARY SCIENCES Veterinary Quarterly Pub Date : 2024-12-01 Epub Date: 2024-01-30 DOI:10.1080/01652176.2024.2305731
Sally J Coggins, Benjamin Kimble, Richard Malik, Mary F Thompson, Jacqueline M Norris, Merran Govendir
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Abstract

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 in vitro feline microsome model with in vitro t1/2 and in vitro Clint 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. In vitro 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 in vitro, 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.

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评估雷米替韦(GS-5734)在猫血浆和全血中的体外稳定性以及向 GS-441524 的转化。
猫传染性腹膜炎(FIP)是一种由冠状病毒引起的潜在致命性猫病。使用核苷类似物 GS-441524 和原药雷米替韦(RDV)治疗可使实验诱发的和自然发生的 FIP 得到缓解,但有关 RDV 在猫体内代谢成 GS-441524 的信息却很少。本研究利用体外猫科动物微粒体模型,采用底物耗竭法计算体外 t1/2 和体外 Clint,评估了 RDV 在猫体内可能的 I 期代谢。利用之前经过验证的高效液相色谱 (HPLC) 荧光法检测和分析 RDV 和 GS-441524。在微粒体培养后测定了 RDV 和中间代谢产物 GS-441524 的定性产量,然后与全血和血浆培养进行了比较。体外微粒体培养导致 RDV 快速消耗,但在猫体内似乎不像在人和狗体内那样发生传统的 I 期依赖性反应。在体外全血中,RDV 被消耗为 GS-441524,这表明猫可能通过血液酯酶将 RDV 转化为 GS-441524,正如在小鼠和大鼠身上观察到的那样。RDV 代谢不太可能受到猫肝功能受损的影响。此外,由于 RDV 会在数分钟内消耗殆尽,而 GS-441524 却非常稳定,因此全血或血浆中 GS-441524 的浓度,而不是血浆中 RDV 的浓度,更适合用于接受 RDV 的猫的治疗药物监测 (TDM)。
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来源期刊
Veterinary Quarterly
Veterinary Quarterly VETERINARY SCIENCES-
CiteScore
13.10
自引率
1.60%
发文量
18
审稿时长
>24 weeks
期刊介绍: Veterinary Quarterly is an international open access journal which publishes high quality review articles and original research in the field of veterinary science and animal diseases. The journal publishes research on a range of different animal species and topics including: - Economically important species such as domesticated and non-domesticated farm animals, including avian and poultry diseases; - Companion animals (dogs, cats, horses, pocket pets and exotics); - Wildlife species; - Infectious diseases; - Diagnosis; - Treatment including pharmacology and vaccination
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