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

Chang, Cheng-Shang; Peng, Wen-Ya; Lee, Wan-Hsin; Lin, Tsai-Yun; Yang, Muh‐Hwa; Dalley, Jeffrey W.; Tsai, Tung Hu

doi:10.1016/j.ebiom.2023.104748

Cited by 10 publications

(4 citation statements)

References 28 publications

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“…Mishra and Kumar used LC-MS to evaluate placental long-chain polyunsaturated fatty acid transport and metabolism in a rat model of lean gestational diabetes mellitus [ 77 ]. UHPLC-MS/MS has recently been applied to assess whether molnupiravir and the nucleoside analog β-D-N4-hydroxycytidine could cross the blood–placenta barrier into the fetus [ 78 ]. ICP-MS was also used to evaluate the placenta transfer of the trace metal cobalt (Co) from mother to fetus in 246 mother–infant pairs from a case–control study on birth defects [ 79 ].…”

Section: Resultsmentioning

confidence: 99%

Fetus Exposure to Drugs and Chemicals: A Holistic Overview on the Assessment of Their Transport and Metabolism across the Human Placental Barrier

Kotta-Loizou,

Pritsa,

Antasouras

et al. 2024

Diseases

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Background: The placenta exerts a crucial role in fetus growth and development during gestation, protecting the fetus from maternal drugs and chemical exposure. However, diverse drugs and chemicals (xenobiotics) can penetrate the maternal placental barrier, leading to deleterious, adverse effects concerning fetus health. Moreover, placental enzymes can metabolize drugs and chemicals into more toxic compounds for the fetus. Thus, evaluating the molecular mechanisms through which drugs and chemicals transfer and undergo metabolism across the placental barrier is of vital importance. In this aspect, this comprehensive literature review aims to provide a holistic approach by critically summarizing and scrutinizing the potential molecular processes and mechanisms governing drugs and chemical transfer and metabolism across the placental barrier, which may lead to fetotoxicity effects, as well as analyzing the currently available experimental methodologies used to assess xenobiotics placental transfer and metabolism. Methods: A comprehensive and in-depth literature review was conducted in the most accurate scientific databases such as PubMed, Scopus, and Web of Science by using relevant and effective keywords related to xenobiotic placental transfer and metabolism, retrieving 8830 published articles until 5 February 2024. After applying several strict exclusion and inclusion criteria, a final number of 148 relevant published articles were included. Results: During pregnancy, several drugs and chemicals can be transferred from the mother to the fetus across the placental barrier by either passive diffusion or through placental transporters, resulting in fetus exposure and potential fetotoxicity effects. Some drugs and chemicals also appear to be metabolized across the placental barrier, leading to more toxic products for both the mother and the fetus. At present, there is increasing research development of diverse experimental methodologies to determine the potential molecular processes and mechanisms of drug and chemical placental transfer and metabolism. All the currently available methodologies have specific strengths and limitations, highlighting the strong demand to utilize an efficient combination of them to obtain reliable evidence concerning drug and chemical transfer and metabolism across the placental barrier. To derive the most consistent and safe evidence, in vitro studies, ex vivo perfusion methods, and in vivo animal and human studies can be applied together with the final aim to minimize potential fetotoxicity effects. Conclusions: Research is being increasingly carried out to obtain an accurate and safe evaluation of drug and chemical transport and metabolism across the placental barrier, applying a combination of advanced techniques to avoid potential fetotoxic effects. The improvement of the currently available techniques and the development of novel experimental protocols and methodologies are of major importance to protect both the mother and the fetus from xenobiotic exposure, as well as to minimize potential fetotoxicity effects.

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Section: Resultsmentioning

confidence: 99%

Fetus Exposure to Drugs and Chemicals: A Holistic Overview on the Assessment of Their Transport and Metabolism across the Human Placental Barrier

Kotta-Loizou,

Pritsa,

Antasouras

et al. 2024

Diseases

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“…The immediate development of new drugs and vaccines is critical and time-consuming, due to which repurposing of existing antiviral drugs has gained momentum in drug discovery research. The claudine, N 4-hydroxycytidine (EIDD-1931), 2′- C -methylcytidine, molnupiravir, uprifosbuvir, balapiravir, acalabrutinib, BMS-986094, remdesivir, GS-6620, and ceforanide are being explored for their potential effectiveness against coronavirus and other viruses. , Molnupiravir is a promising antiviral agent for the current coronavirus and future viral threats. It is an antiviral drug initially developed for influenza treatment and has also shown promising activity against several RNA viruses, including SARS-CoV-2, − developed by Drive and later acquired by Ridgeback Biotherapeutics comarketed with Merck as MK-4482. − Numerous scientific groups from academia and the pharmaceutical industry have dedicated significant efforts to develop new synthetic routes for manufacturing Molnupiravir (Scheme ).…”

Section: Introductionmentioning

confidence: 99%

“…The claudine, N 4-hydroxycytidine (EIDD-1931), 2′- C -methylcytidine, molnupiravir, uprifosbuvir, balapiravir, acalabrutinib, BMS-986094, remdesivir, GS-6620, and ceforanide are being explored for their potential effectiveness against coronavirus and other viruses. 1 , 2 Molnupiravir is a promising antiviral agent for the current coronavirus and future viral threats. It is an antiviral drug initially developed for influenza treatment and has also shown promising activity against several RNA viruses, including SARS-CoV-2, 3 − 5 developed by Drive and later acquired by Ridgeback Biotherapeutics comarketed with Merck as MK-4482.…”

Section: Introductionmentioning

confidence: 99%

Streamlined Chemo-Enzymatic Synthesis of Molnupiravir via Lipase Catalyst

Rosangzuala,

Patlolla,

Shaikh

et al. 2024

ACS Omega

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An enzymatic approach for the synthesis of Molnupiravir has been developed using immobilized lipase as a biocatalyst. This method involves a concise process of the regioselective esterification of uridine with isobutyric anhydride using Lipase (Addzyme-011). This efficient route gets 97% conversion of uridine 3, with an overall 73% yield of molnupiravir 1 in two steps. The use of inexpensive and easily available lipase makes the synthesis cost-effective and accessible globally, promoting the principles of green chemistry.

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“…NHC does not bind to blood proteins, and is eliminated from the body by the metabolism through pyrimidine metabolic pathways [ 16 ]. Molnupiravir is rapidly absorbed from the gastrointestinal tract, and is capable of effectively crossing the hematoencephalic barrier [ 17 ]. NHC is not a substrate, an inhibitor, or an inducer of transport proteins, CYP enzymes, or P-glycoprotein [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Development and Validation of a High-Performance Liquid Chromatography with Tandem Mass Spectrometry (HPLC-MS/MS) Method for Quantification of Major Molnupiravir Metabolite (β-D-N4-hydroxycytidine) in Human Plasma

Komarov,

Karnakova,

Archakova

et al. 2023

Biomedicines

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Molnupiravir is an antiviral drug against viral RNA polymerase activity approved by the FDA for the treatment of COVID-19, which is metabolized to β-D-N4-hydroxycytidine (NHC) in human blood plasma. A novel method was developed and validated for quantifying NHC in human plasma within the analytical range of 10–10,000 ng/mL using high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS) to support pharmacokinetics studies. For sample preparation, the method of protein precipitation by acetonitrile was used, with promethazine as an internal standard. Chromatographic separation was carried out on a Shim-pack GWS C18 (150 mm × 4.6 mm, 5 μm) column in a gradient elution mode. A 0.1% formic acid solution in water with 0.08% ammonia solution (eluent A, v/v) and 0.1% formic acid solution in methanol with 0.08% ammonia solution mixed with acetonitrile in a 4:1 ratio (eluent B, v/v) were used as a mobile phase. Electrospray ionization (ESI) was used as an ionization source. The developed method was validated in accordance with the Eurasian Economic Union (EAEU) rules, based on the European Medicines Agency (EMA) and Food and Drug Administration (FDA) guidelines for the following parameters and used within the analytical part of the clinical study of molnupiravir drugs: selectivity, suitability of standard sample, matrix effect, calibration curve, accuracy, precision, recovery, lower limit of quantification (LLOQ), carryover, and stability.

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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

Cited by 10 publications

References 28 publications

Fetus Exposure to Drugs and Chemicals: A Holistic Overview on the Assessment of Their Transport and Metabolism across the Human Placental Barrier

Fetus Exposure to Drugs and Chemicals: A Holistic Overview on the Assessment of Their Transport and Metabolism across the Human Placental Barrier

Streamlined Chemo-Enzymatic Synthesis of Molnupiravir via Lipase Catalyst

Development and Validation of a High-Performance Liquid Chromatography with Tandem Mass Spectrometry (HPLC-MS/MS) Method for Quantification of Major Molnupiravir Metabolite (β-D-N4-hydroxycytidine) in Human Plasma

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