Biotransformation and transplacental transfer of the anti-viral remdesivir and predominant metabolite, GS-441524 in pregnant rats

Yang, Ling; Lin, I-Hsin; Lin, Lie‐Chwen; Dalley, Jeffrey W.; Tsai, Tung Hu

doi:10.1016/j.ebiom.2022.104095

Cited by 11 publications

(9 citation statements)

References 34 publications

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“… 33 , 34 A previous study revealed that the conceptus concentration was approximately the effective concentration at the therapeutic dose after remdesivir administration (30 mg/kg, i.v.). 32 Although molnupiravir and remdesivir have different therapeutic efficacies and associated adverse effects, our data support the notion that both antivirus drugs reach effective concentrations for SARS-CoV-2 at regular doses of remdesivir (30 mg/kg, i.v.) and molnupiravir administration (100 mg/kg, i.v.).…”

Section: Discussionsupporting

confidence: 77%

“…Compared to molnupiravir, a previous report demonstrated that a metabolite of remdesivir, GS-441524, was rapidly transferred to the placenta with a transfer ratio from mother to fetus of 0.51 ± 0.18, a transfer ratio from mother to placenta of 0.35 ± 0.09, and a transfer ratio from mother to amniotic fluid of 0.71 ± 0.19 after remdesivir administration (30 mg/kg, i.v.). 32 Furthermore, the EC 50 of GS-441524 was observed to be 0.18 μM (equivalent to 46.8 ng/mL) in human airway epithelial cells (HAE). 33 , 34 A previous study revealed that the conceptus concentration was approximately the effective concentration at the therapeutic dose after remdesivir administration (30 mg/kg, i.v.).…”

Section: Discussionmentioning

confidence: 98%

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Transfer and biotransformation of the COVID-19 prodrug molnupiravir and its metabolite β-D-N4-hydroxycytidine across the blood-placenta barrier

Chang¹,

Peng²,

Lee³

et al. 2023

eBioMedicine

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 98%

Transfer and biotransformation of the COVID-19 prodrug molnupiravir and its metabolite β-D-N4-hydroxycytidine across the blood-placenta barrier

Chang¹,

Peng²,

Lee³

et al. 2023

eBioMedicine

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“…This suggests that RDV is more quickly metabolized to GS-441524 in rats and rabbits than in humans (C max of GS-441524 in the latter is 0.48-0.52 μM; Humeniuk et al, 2020;Tempestilli et al, 2020). A recent study using pregnant rats has also shown that RDV becomes undetectable in the maternal plasma at 40 min after administration, confirming the rapid metabolism and elimination of RDV (Yang, Lin, Lin, Dalley, & Tsai, 2022). This may also be the case for the mouse, in which the plasma C max of RDV (<1 μM) is considerably lower than that of GS-441524 (35.8 μM) (Hu et al, 2021).…”

Section: Discussionmentioning

confidence: 88%

Developmental toxicity of remdesivir, an anti‐COVID‐19 drug, is implicated by in vitro assays using morphogenetic embryoid bodies of mouse and human pluripotent stem cells

Kirkwood-Johnson

Marikawa

2022

Birth Defects Research

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Background Remdesivir is an antiviral drug approved for the treatment of COVID‐19, whose developmental toxicity remains unclear. More information about the safety of remdesivir is urgently needed for people of childbearing potential, who are affected by the ongoing pandemic. Morphogenetic embryoid bodies (MEBs) are three‐dimensional (3D) aggregates of pluripotent stem cells that recapitulate embryonic body patterning in vitro, and have been used as effective embryo models to detect the developmental toxicity of chemical exposures specifically and sensitively. Methods MEBs were generated from mouse P19C5 and human H9 pluripotent stem cells, and used to examine the effects of remdesivir. The morphological effects were assessed by analyzing the morphometric parameters of MEBs after exposure to varying concentrations of remdesivir. The molecular impact of remdesivir was evaluated by measuring the transcript levels of developmental regulator genes. Results The mouse MEB morphogenesis was impaired by remdesivir at 1–8 μM. Remdesivir affected MEBs in a manner dependent on metabolic conversion, and its potency was higher than GS‐441524 and GS‐621763, presumptive anti‐COVID‐19 drugs that act similarly to remdesivir. The expressions of developmental regulator genes, particularly those involved in axial and somite patterning, were dysregulated by remdesivir. The early stage of MEB development was more vulnerable to remdesivir exposure than the later stage. The morphogenesis and gene expression profiles of human MEBs were also impaired by remdesivir at 1–8 μM. Conclusions Remdesivir impaired mouse and human MEBs at concentrations that are comparable to the therapeutic plasma levels in humans, urging further investigation into the potential impact of remdesivir on developing embryos.

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“…( 36 ) showed that GS-441524, a promising RdRp inhibitor, demonstrated adequate intracellular conversion into active triphosphate (GS-443902, 42.7–100 nmol/L) in the lungs of CD-1 mice upon oral administration. Furthermore, GS-441524 does not exhibit preferential hepatic metabolism because it is not a substrate for human microsomal hepatic cytochrome P450 (CYPs 1A1, 1A2, 3A4, 3A5, 2B6, 2C8, 2C9, 2C19, and 2D6) ( 106 ). Li et al.…”

Section: The Orally Administered Versions Of Gs-441524mentioning

confidence: 99%

Oral GS-441524 derivatives: Next-generation inhibitors of SARS‐CoV‐2 RNA‐dependent RNA polymerase

Wang

Yang

Song³

2022

Front. Immunol.

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GS-441524, an RNA‐dependent RNA polymerase (RdRp) inhibitor, is a 1′-CN-substituted adenine C-nucleoside analog with broad-spectrum antiviral activity. However, the low oral bioavailability of GS‐441524 poses a challenge to its anti-SARS-CoV-2 efficacy. Remdesivir, the intravenously administered version (version 1.0) of GS-441524, is the first FDA-approved agent for SARS-CoV-2 treatment. However, clinical trials have presented conflicting evidence on the value of remdesivir in COVID-19. Therefore, oral GS-441524 derivatives (VV116, ATV006, and GS-621763; version 2.0, targeting highly conserved viral RdRp) could be considered as game-changers in treating COVID-19 because oral administration has the potential to maximize clinical benefits, including decreased duration of COVID-19 and reduced post-acute sequelae of SARS-CoV-2 infection, as well as limited side effects such as hepatic accumulation. This review summarizes the current research related to the oral derivatives of GS-441524, and provides important insights into the potential factors underlying the controversial observations regarding the clinical efficacy of remdesivir; overall, it offers an effective launching pad for developing an oral version of GS-441524.

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Biotransformation and transplacental transfer of the anti-viral remdesivir and predominant metabolite, GS-441524 in pregnant rats

Cited by 11 publications

References 34 publications

Transfer and biotransformation of the COVID-19 prodrug molnupiravir and its metabolite β-D-N4-hydroxycytidine across the blood-placenta barrier

Transfer and biotransformation of the COVID-19 prodrug molnupiravir and its metabolite β-D-N4-hydroxycytidine across the blood-placenta barrier

Developmental toxicity of remdesivir, an anti‐COVID‐19 drug, is implicated by in vitro assays using morphogenetic embryoid bodies of mouse and human pluripotent stem cells

Oral GS-441524 derivatives: Next-generation inhibitors of SARS‐CoV‐2 RNA‐dependent RNA polymerase

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