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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

BACKGROUND: Molnupiravir is an orally bioavailable prodrug of the nucleoside analogue β-D-N4-hydroxycytidine (NHC) and is used to treat coronavirus disease 2019 (COVID-19). However, the pharmacokinetics and transplacental transfer of molnupiravir in pregnant women are still not well understood. In t...

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Autores principales: Chang, Chun-Hao, Peng, Wen-Ya, Lee, Wan-Hsin, Lin, Tung-Yi, Yang, Muh-Hwa, Dalley, Jeffrey W., Tsai, Tung-Hu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10427982/
https://www.ncbi.nlm.nih.gov/pubmed/37544201
http://dx.doi.org/10.1016/j.ebiom.2023.104748
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author Chang, Chun-Hao
Peng, Wen-Ya
Lee, Wan-Hsin
Lin, Tung-Yi
Yang, Muh-Hwa
Dalley, Jeffrey W.
Tsai, Tung-Hu
author_facet Chang, Chun-Hao
Peng, Wen-Ya
Lee, Wan-Hsin
Lin, Tung-Yi
Yang, Muh-Hwa
Dalley, Jeffrey W.
Tsai, Tung-Hu
author_sort Chang, Chun-Hao
collection PubMed
description BACKGROUND: Molnupiravir is an orally bioavailable prodrug of the nucleoside analogue β-D-N4-hydroxycytidine (NHC) and is used to treat coronavirus disease 2019 (COVID-19). However, the pharmacokinetics and transplacental transfer of molnupiravir in pregnant women are still not well understood. In the present study, we investigated the hypothesis that molnupiravir and NHC cross the blood-placenta barrier into the fetus. METHODS: A multisite microdialysis coupled with a validated ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC‒MS/MS) system was developed to monitor the dialysate levels of molnupiravir and NHC in maternal rat blood and conceptus (the collective term for the fetus, placenta, and amniotic fluid). Molnupiravir was administered intravenously (100 mg/kg, i.v.) on gestational day 16. To investigate the mechanism of transport of molnupiravir across the blood-placenta barrier, we coadministered nitrobenzylthioinosine (NBMPR, 10 mg/kg, i.v.) to inhibit equilibrative nucleoside transporter (ENT). FINDINGS: We report that molnupiravir is rapidly metabolized to NHC and then rapidly transformed in the fetus, placenta, amniotic fluid, and maternal blood. Our pharmacokinetics analysis revealed that the area under the concentration curve (AUC) for the mother-to-fetus ratio (AUC(fetus)/AUC(blood)) of NHC was 0.29 ± 0.11. Further, we demonstrated that the transport of NHC in the placenta may not be subject to modulation by the ENT. INTERPRETATION: Our results show that NHC is the predominant bioactive metabolite of molnupiravir and rapidly crosses the blood-placenta barrier in pregnant rats. The NHC concentration in maternal blood and conceptus was above the average median inhibitory concentration (IC(50)) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), suggesting a therapeutic effect. These findings support the use of molnupiravir in pregnant patients infected with COVID. FUNDING: This study was supported in part by research grants from the National Science and Technology Council of Taiwan (NSTC 111-2113-M-A49-018 and NSTC 112-2321-B-A49-005).
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spelling pubmed-104279822023-08-17 Transfer and biotransformation of the COVID-19 prodrug molnupiravir and its metabolite β-D-N4-hydroxycytidine across the blood-placenta barrier Chang, Chun-Hao Peng, Wen-Ya Lee, Wan-Hsin Lin, Tung-Yi Yang, Muh-Hwa Dalley, Jeffrey W. Tsai, Tung-Hu eBioMedicine Articles BACKGROUND: Molnupiravir is an orally bioavailable prodrug of the nucleoside analogue β-D-N4-hydroxycytidine (NHC) and is used to treat coronavirus disease 2019 (COVID-19). However, the pharmacokinetics and transplacental transfer of molnupiravir in pregnant women are still not well understood. In the present study, we investigated the hypothesis that molnupiravir and NHC cross the blood-placenta barrier into the fetus. METHODS: A multisite microdialysis coupled with a validated ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC‒MS/MS) system was developed to monitor the dialysate levels of molnupiravir and NHC in maternal rat blood and conceptus (the collective term for the fetus, placenta, and amniotic fluid). Molnupiravir was administered intravenously (100 mg/kg, i.v.) on gestational day 16. To investigate the mechanism of transport of molnupiravir across the blood-placenta barrier, we coadministered nitrobenzylthioinosine (NBMPR, 10 mg/kg, i.v.) to inhibit equilibrative nucleoside transporter (ENT). FINDINGS: We report that molnupiravir is rapidly metabolized to NHC and then rapidly transformed in the fetus, placenta, amniotic fluid, and maternal blood. Our pharmacokinetics analysis revealed that the area under the concentration curve (AUC) for the mother-to-fetus ratio (AUC(fetus)/AUC(blood)) of NHC was 0.29 ± 0.11. Further, we demonstrated that the transport of NHC in the placenta may not be subject to modulation by the ENT. INTERPRETATION: Our results show that NHC is the predominant bioactive metabolite of molnupiravir and rapidly crosses the blood-placenta barrier in pregnant rats. The NHC concentration in maternal blood and conceptus was above the average median inhibitory concentration (IC(50)) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), suggesting a therapeutic effect. These findings support the use of molnupiravir in pregnant patients infected with COVID. FUNDING: This study was supported in part by research grants from the National Science and Technology Council of Taiwan (NSTC 111-2113-M-A49-018 and NSTC 112-2321-B-A49-005). Elsevier 2023-08-04 /pmc/articles/PMC10427982/ /pubmed/37544201 http://dx.doi.org/10.1016/j.ebiom.2023.104748 Text en © 2023 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Articles
Chang, Chun-Hao
Peng, Wen-Ya
Lee, Wan-Hsin
Lin, Tung-Yi
Yang, Muh-Hwa
Dalley, Jeffrey W.
Tsai, Tung-Hu
Transfer and biotransformation of the COVID-19 prodrug molnupiravir and its metabolite β-D-N4-hydroxycytidine across the blood-placenta barrier
title Transfer and biotransformation of the COVID-19 prodrug molnupiravir and its metabolite β-D-N4-hydroxycytidine across the blood-placenta barrier
title_full Transfer and biotransformation of the COVID-19 prodrug molnupiravir and its metabolite β-D-N4-hydroxycytidine across the blood-placenta barrier
title_fullStr Transfer and biotransformation of the COVID-19 prodrug molnupiravir and its metabolite β-D-N4-hydroxycytidine across the blood-placenta barrier
title_full_unstemmed Transfer and biotransformation of the COVID-19 prodrug molnupiravir and its metabolite β-D-N4-hydroxycytidine across the blood-placenta barrier
title_short Transfer and biotransformation of the COVID-19 prodrug molnupiravir and its metabolite β-D-N4-hydroxycytidine across the blood-placenta barrier
title_sort transfer and biotransformation of the covid-19 prodrug molnupiravir and its metabolite β-d-n4-hydroxycytidine across the blood-placenta barrier
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10427982/
https://www.ncbi.nlm.nih.gov/pubmed/37544201
http://dx.doi.org/10.1016/j.ebiom.2023.104748
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