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

EBioMedicine

Tung-Hu Tsai¹  Jeffrey W. Dalley²  I-Hsin Lin³  Ling Yang³  Lie-Chwen Lin⁴ 

[1] Department of Psychiatry, University of Cambridge, Cambridge CB2 0SZ, United Kingdom;Department of Psychology, University of Cambridge, Cambridge CB2 3EB, United Kingdom;Institute of Traditional Medicine, School of Medicine, National Yang Ming Chiao Tung University, Li-Nong Street Section 2, Taipei 112, Taiwan;National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei 112, Taiwan;

关键词: Remdesivir;    GS-441524;    Microdialysis;    Blood-placental barrier;    Pharmacokinetics;   

DOI  :  

来源: DOAJ

【 摘 要 】

Summary:Background: Remdesivir was the first prodrug approved to treat coronavirus disease 2019 (COVID-19) and has the potential to be used during pregnancy. However, it is not known whether remdesivir and its main metabolite, GS-441524 have the potential to cross the blood-placental barrier. We hypothesize that remdesivir and predominant metabolite GS-441524may cross the blood-placental barrier to reach the embryo tissues. Methods: To test this hypothesis, ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) coupled with multisite microdialysis was used to monitor the levels of remdesivir and the nucleoside analogue GS-441524 in the maternal blood, fetus, placenta, and amniotic fluid of pregnant Sprague-Dawley rats. The transplacental transfer was evaluated using the pharmacokinetic parameters of AUC and mother-to-fetus transfer ratio (AUCfetus/AUCmother). Findings: Our in-vivo results show that remdesivir is rapidly biotransformed into GS-441524 in the maternal blood, which then readily crossed the placenta with a mother-to-fetus transfer ratio of 0.51 ± 0.18. The Cmax and AUClast values of GS-441524 followed the order: maternal blood > amniotic fluid > fetus > placenta in rats. Interpretation: While remdesivir does not directly cross into the fetus, however, its main metabolite, GS-441524 readily crosses the placenta and can reside there for at least 4 hours as shown in the pregnant Sprague-Dawley rat model. These findings suggest that careful consideration should be taken for the use of remdesivir in the treatment of COVID-19 in pregnancy. Funding: Ministry of Science and Technology of Taiwan.

【 授权许可】

Unknown