背景:Molnupiravir是核苷类似物β-D-N4-羟基胞苷(NHC)的口服生物可利用前药,用于治疗2019年冠状病毒病(COVID-19)。然而,孕妇中莫那普拉韦的药代动力学和胎盘转移仍未得到很好的了解。在本研究中,我们调查了molnupiravir和NHC穿过血胎盘屏障进入胎儿的假设。
方法:开发了一种多点微透析与经过验证的超高效液相色谱-串联质谱(UHPLC-MS/MS)系统,以监测母体大鼠血液和概念中molnupiravir和NHC的透析液水平(胎儿的统称,胎盘,和羊水)。Molnupiravir静脉注射(100mg/kg,i.v.)在妊娠第16天。探讨莫诺比拉韦穿越血胎盘屏障的转运机制,我们共同给药硝基苄硫基肌苷(NBMPR,10mg/kg,i.v.)抑制平衡核苷转运蛋白(ENT)。
结果:我们报告说,莫诺比拉韦迅速代谢为NHC,然后在胎儿中迅速转化,胎盘,羊水,母亲的血。我们的药代动力学分析显示,NHC的母胎比(AUCFuteutor/AUCblood)的浓度曲线下面积(AUC)为0.29±0.11。Further,我们证明了NHC在胎盘中的转运可能不受ENT的调节。
结论:我们的结果表明,NHC是莫诺比拉韦的主要生物活性代谢产物,并在妊娠大鼠中快速穿过血液-胎盘屏障。母体血液和概念中的NHC浓度高于严重急性呼吸综合征冠状病毒2(SARS-CoV-2)的平均中位抑制浓度(IC50),表明有治疗效果.这些发现支持在感染COVID的怀孕患者中使用莫努比拉韦。
背景:本研究部分得到了台湾国家科学技术委员会的研究资助(NSTC111-2113-M-A49-018和NSTC112-2321-B-A49-005)。
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).
RESULTS: 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 (AUCfetus/AUCblood) 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.
CONCLUSIONS: 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 (IC50) 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.
BACKGROUND: 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).