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What metabolism occurs in the liver to make remdesivir inactive if taken orally?

Comment by InpharmD Researcher

Due to high first-pass hepatic extraction of phosphoramidates, remdesivir is predicted to have poor oral bioavailability. Other ribonucleoside analogues that have oral bioavailability are being developed.
Background

Remdesivir, an RNA dependent RNA polymerase (RdRp) inhibitor, is a phosphoramidate prodrug of a 1’-cyano-substituted nucleoside analogue. Nucleoside phosphoramidates, like remdesivir, must be administered as prodrugs to mask the charged phosphonate group and allow faster cell entry because they are not very permeable into cells. Once inside cells, remdesivir undergoes rapid metabolic conversion by intracellular kinases to its active nucleoside triphosphate metabolite. With remdesivir, the negative charge is masked by the 2-ethylbutyl and L-alanine groups which are rapidly removed by intracellular esterases. [1-3]

Due to the near-complete first-pass effect of phosphoramidates, remdesivir is expected to have poor oral bioavailability. Plasma protein binding for remdesivir is moderate, while remdesivir's metabolites exhibit low plasma protein binding with mean free fractions ≥ 85%. Remdesivir is a substrate of several cytochrome P450 enzymes in vitro; however, clinical implications are unclear since the prodrug is rapidly metabolized by plasma hydrolases. The effect of hepatic impairment on remdesivir plasma concentrations should be low although specific studies have not been conducted in patients with hepatic impairment and the drug is contraindicated in patients with severe hepatic impairment. [1-3]

Following diffusion into the cell, the remdesivir is metabolized in a sequence of hydrolytic steps starting with esterase-mediated ester hydrolysis to a carboxylate that cyclizes internally to the phosphonate ejecting the phenoxide. Nucleoside monophosphate which is highly polar can not diffuse back across the membrane which essentially traps it within the cell. The nucleoside analogue core of remdesivir can diffuse into cells; however, the initial phosphorylation step for nucleosides is rate-limiting (slow) this accounts for its reduced antiviral activity compared to the whole remdesivir molecule. [1-3]

Another ribonucleoside analog β-d-N4-hydroxycytidine has in vitro activity against SARS-CoV-2 and in vivo against the related SARS virus. It is orally bioavailable and has increased potency against viruses containing mutations in RdRp that confer resistance to remdesivir. [1]

References:

[1] Eastman RT, Roth JS, Brimacombe KR, et al. Remdesivir: A Review of Its Discovery and Development Leading to Emergency Use Authorization for Treatment of COVID-19. ACS Cent Sci. 2020;6(5):672‐683.
[2] Jorgensen S, Kebriaei R, Dresser L. Remdesivir: Review of pharmacology, pre‐clinical data and emerging clinical experience for COVID‐19. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy. 2020;[E-pub ahead of print].
[3] Siegel D, Hui HC, Doerffler E, 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(5):1648-1661.