Abstract
Remdesivir (RDV) exerts anti-severe acute respiratory coronavirus 2 activity following metabolic activation in the target tissues. However, the pharmacokinetics and tissue distributions of the parent drug and its active metabolites have been poorly characterized to date. Blood and tissue levels were evaluated in the current study. After intravenous administration of 20 mg/kg RDV in mice, the concentrations of the parent drug, nucleotide monophosphate (RMP) and triphosphate (RTP), as well as nucleoside (RN), in the blood, heart, liver, lung, kidney, testis, and small intestine were quantified. In blood, RDV was rapidly and completely metabolized and was barely detected at 0.5 h, similar to RTP, while its metabolites RMP and RN exhibited higher blood levels with increased residence times. The area under the concentration versus time curve up to the last measured point in time (AUC0-t) values of RMP and RN were 4558 and 136,572 h∙nM, respectively. The maximum plasma concentration (Cmax) values of RMP and RN were 2896 nM and 35,819 nM, respectively. Moreover, RDV presented an extensive distribution, and the lung, liver and kidney showed high levels of the parent drug and metabolites. The metabolic stabilities of RDV and RMP were also evaluated using lung, liver, and kidney microsomes. RDV showed higher clearances in the liver and kidney than in the lung, with intrinsic clearance (CLint) values of 1740, 1253, and 127 mL/(min∙g microsomal protein), respectively.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020;323:1061–9.
Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020;382:727–33.
Holshue ML, DeBolt C, Lindquist S, Lofy KH, Wiesman J, Bruce H, et al. First case of 2019 novel coronavirus in the United States. N Engl J Med. 2020;382:929–36.
World Health Organization. WHO Coronavirus Disease (COVID-19) Dashboard [updated 2020 Jul 29; cited 2020 Jul 30]. https://covid19.who.int/.
Bajwah S, Wilcock A, Towers R, Costantini M, Bausewein C, Simon ST, et al. Managing the supportive care needs of those affected by COVID-19. Eur Respir J. 2020;55:2000815.
Sheahan TP, Sims AC, Zhou S, Graham RL, Pruijssers AJ, Agostini ML, et al. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Sci Transl Med. 2020;12:eabb5883.
Warren TK, Jordan R, Lo MK, Ray AS, Mackman RL, Soloveva V, et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature. 2016;531:381–5.
Brown AJ, Won JJ, Graham RL, Dinnon KH 3rd, Sims AC, Feng JY, et al. Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase. Antivir Res. 2019;169:104541.
Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A, et al. Compassionate use of remdesivir for patients with severe Covid-19. N Engl J Med. 2020;382:2327–36.
Firstenberg MS, Stahel PF, Hanna J, Kotaru C, Crossno J Jr, Forrester J. Successful COVID-19 rescue therapy by extra-corporeal membrane oxygenation (ECMO) for respiratory failure: a case report. Patient Saf Surg. 2020;14:20.
Sheahan TP, Sims AC, Graham RL, Menachery VD, Gralinski LE, Case JB, et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med. 2017;9:eaal3653.
Siegel D, Hui HC, Doerffler E, Clarke MO, Chun K, Zhang L, et al. Discovery and synthesis of a phosphoramidate prodrug of a pyrrolo[2,1-f][triazin-4-amino] adenine c-nucleoside (GS-5734) for the treatment of Ebola and emerging viruses. J Med Chem. 2017;60:1648–61.
Yin W, Mao C, Luan X, Shen DD, Shen Q, Su H, et al. Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir. Science. 2020;368:1499–504.
Sabatini DD. Subcellular fractionation of rough microsomes. Cold Spring Harb Protoc. 2014;2014:932–4.
Food and Drug Administration (US). Bioanalytical method validation guidance for industry. 2018 May [cited 2020 Jul 30]. https://www.fda.gov/media/70858/download.
European Medicines Agency. Summary on compassionate use: Remdesivir Gilead. 2020 Apr 3 [cited 2020 Jul 30]. https://www.ema.europa.eu/en/documents/other/summary-compassionate-use-remdesivir-gilead_en.pdf.
Li B, Sedlacek M, Manoharan I, Boopathy R, Duysen EG, Masson P, et al. Butyrylcholinesterase, paraoxonase, and albumin esterase, but not carboxylesterase, are present in human plasma. Biochem Pharmacol. 2005;70:1673–84.
Jorgensen SCJ, Kebriaei R, Dresser LD. Remdesivir: review of pharmacology, pre-clinical data, and emerging clinical experience for COVID-19. Pharmacotherapy. 2020;40:659–71.
Kirby BJ, Symonds WT, Kearney BP, Mathias AA. Pharmacokinetic, pharmacodynamic, and drug-interaction profile of the hepatitis C virus NS5B polymerase inhibitor sofosbuvir. Clin Pharmacokinet. 2015;54:677–90.
Bourgonje AR, Abdulle AE, Timens W, Hillebrands JL, Navis GJ, Gordijn SJ, et al. Angiotensin-converting enzyme-2 (ACE2), SARS-CoV-2 and pathophysiology of coronavirus disease 2019 (COVID-19). J Pathol. 2020;251:228–48.
Wang Z, Xu X. scRNA-seq profiling of human testes reveals the presence of the ACE2 receptor, a target for SARS-CoV-2 infection in spermatogonia, leydig and sertoli cells. Cells. 2020;9:920.
Babusis D, Curry MP, Kirby B, Park Y, Murakami E, Wang T, et al. Sofosbuvir and ribavirin liver pharmacokinetics in patients infected with hepatitis C virus. Antimicrob Agents Chemother. 2018;62:e02587–17.
Zhang J, Dean RA, Brzezinski MR, Bosron WF. Gender-specific differences in activity and protein levels of cocaine carboxylesterase in rat tissues. Life Sci. 1996;59:1175–84.
Gabriele M, Puccini P, Lucchi M, Vizziello A, Gervasi PG, Longo V. Presence and inter-individual variability of carboxylesterases (CES1 and CES2) in human lung. Biochem Pharmacol. 2018;150:64–71.
Ishizuka T, Yoshigae Y, Murayama N, Izumi T. Different hydrolases involved in bioactivation of prodrug-type angiotensin receptor blockers: carboxymethylenebutenolidase and carboxylesterase 1. Drug Metab Dispos. 2013;41:1888–95.
Acknowledgements
This study was supported by the Youth Innovation Promotion Association of the Chinese Academy of Sciences (2016263).
Author information
Authors and Affiliations
Contributions
JL and BT designed research; WJH, LC, YY, and XW performed research; YCX and JSS contributed chemical synthesis; WJH, LC and JL analyzed data; WJH, BT and JL wrote the paper.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Supplementary information
Rights and permissions
About this article
Cite this article
Hu, Wj., Chang, L., Yang, Y. et al. Pharmacokinetics and tissue distribution of remdesivir and its metabolites nucleotide monophosphate, nucleotide triphosphate, and nucleoside in mice. Acta Pharmacol Sin 42, 1195–1200 (2021). https://doi.org/10.1038/s41401-020-00537-9
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/s41401-020-00537-9
Keywords
This article is cited by
-
Novel immunomodulatory properties of adenosine analogs promote their antiviral activity against SARS-CoV-2
EMBO Reports (2024)
-
Identification of side effects of COVID-19 drug candidates on embryogenesis using an integrated zebrafish screening platform
Scientific Reports (2023)
-
Activation of the urotensin-II receptor by remdesivir induces cardiomyocyte dysfunction
Communications Biology (2023)
-
A population pharmacokinetic model of remdesivir and its major metabolites based on published mean values from healthy subjects
Naunyn-Schmiedeberg's Archives of Pharmacology (2023)
-
The potential of remdesivir to affect function, metabolism and proliferation of cardiac and kidney cells in vitro
Archives of Toxicology (2022)
