Molnupiravir Active Metabolite–N4 hydroxycytidine causes Cytotoxicity to Mammalian Cells In Vitro

Pakotiprapha et al., ASPET 2024 Annual Meeting Abstract - Toxicology, doi:10.1124/jpet.212.937140

May 2024

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In Vitro study showing cytotoxicity of N4-hydroxycytidine (NHC), the active metabolite of molnupiravir, at concentrations relevant to therapeutic doses of molnupiravir in COR-L23 and HepG2 cancer cell lines, and compared with cytotoxicity in normal HaCaT cells. NHC showed cytotoxicity in all three lines, with HaCaT cells showing lower IC₅₀ values compared to both cancer cell lines at 3 and 5 days of treatment. The therapeutic dose of molnupiravir results in serum NHC concentrations close to the IC₅₀ values obtained in this study.

Concerns have been raised that the mutagenic mechanism of action may create dangerous variants or cause cancer1-9. Multiple analyses have identified variants potentially created by molnupiravir10-13.

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5. Zibat et al., N4-hydroxycytidine, the active compound of Molnupiravir, promotes SARS-CoV-2 mutagenesis and escape from a neutralizing nanobody, iScience, doi:10.1016/j.isci.2023.107786.sciencedirect.com, doi.org.

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7. Marikawa et al., An active metabolite of the anti-COVID-19 drug molnupiravir impairs mouse preimplantation embryos at clinically relevant concentrations, Reproductive Toxicology, doi:10.1016/j.reprotox.2023.108475.sciencedirect.com, doi.org.

8. Zhou et al., β-D-N4-hydroxycytidine Inhibits SARS-CoV-2 Through Lethal Mutagenesis But Is Also Mutagenic To Mammalian Cells, The Journal of Infectious Diseases, doi:10.1093/infdis/jiab247.oup.com, doi.org.

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10. Fountain-Jones et al., Effect of molnupiravir on SARS-CoV-2 evolution in immunocompromised patients: a retrospective observational study, The Lancet Microbe, doi:10.1016/S2666-5247(23)00393-2.sciencedirect.com, doi.org.

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13. twitter.com, twitter.com/LongDesertTrain/status/1597353291868155906.twitter.com/LongDesertTrain/status/1597353291868155906.

Pakotiprapha et al., 13 May 2024, peer-reviewed, 6 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

This Paper Molnupiravir All

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