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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. | LitMetric

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

EBioMedicine

Institute of Traditional Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan; Graduate Institute of Acupuncture Science, China Medical University, Taichung 404, Taiwan; Department of Chemistry, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; School of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan. Electronic address:

Published: September 2023

AI Article Synopsis

  • Molnupiravir is a prodrug used to treat COVID-19, but its effects and how it transfers to the fetus in pregnant women are not fully understood.* -
  • In a study using pregnant rats, researchers found that Molnupiravir metabolizes quickly into NHC, which crosses the blood-placenta barrier to reach the fetus.* -
  • The concentrations of NHC in both the mother and fetus were found to be potentially effective against SARS-CoV-2, indicating that molnupiravir might be safe and beneficial for treating COVID-19 in pregnant patients.*

Article Abstract

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/AUC) 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) 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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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10427982PMC
http://dx.doi.org/10.1016/j.ebiom.2023.104748DOI Listing

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