药学监护对围产期心理健康具有重要意义,通常以失眠为特征。近年来,褪黑激素受体激动剂(MRAs)和双食欲素受体拮抗剂(DORAs)治疗失眠的处方有所增加;然而,它们在围产期的使用几乎没有报道。在本研究中,我们开发了一种UPLC-MS/MS方法来定量ramelteon,其代谢产物M-II,suvorexant,和人血浆和母乳中的lemborexant,以积累有关MRA和DORA安全性和转移到母乳中的信息。使用乙酸乙酯液-液萃取(LLE)制备血浆和母乳中的MRA(ramelteon和M-II)样品。对于DORA(suvorexant和lemborexant),将具有乙酸乙酯的LLE应用于血浆样品。对于母乳样本,用乙酸乙酯对LLE观察到显著的离子抑制。能够去除磷脂的固相萃取(SPE)盒改善了基质效应。最后,用甲醇和SPE筒进行蛋白质沉淀,InertSep®磷脂去除剂,选择用于母乳样品制备。ACQUITYUPLCBEHC18柱用于分析物分离。使用等度和梯度洗脱洗脱MRA和DORA,分别,并在多反应监测的正模式下使用电喷雾电离进行分析。MRA和DORA的校准曲线范围为0.1-25和0.5-50ng/ml,分别。血浆和母乳样品在该范围内均表现出良好的线性。通过对其准确度和精密度的评价,对该方法进行了验证,基体效应,recovery,结转,稳定性,和稀释完整性。经过验证的方法已成功应用于母乳喂养妇女捐赠的临床样品,并估算了lemborexant(一例)和suvorexant(两例)的牛奶/血浆(M/P)比和相对婴儿剂量(RID)。Lemborexant的M/P比<1,RID为1.05%。舒沃雷生的M/P比<0.1,RID为0.11-0.20%。这种方法将有助于未来研究评估这些药物在母乳喂养期间的安全性。
Pharmaceutical care is important for mental health during the perinatal period, which is often characterized by insomnia. In recent years, prescriptions of melatonin receptor agonists (MRAs) and dual orexin receptor antagonists (DORAs) for insomnia have increased; however, their use during the perinatal period has scarcely been reported. In the present study, we developed a UPLC-MS/MS method for the quantification of ramelteon, its metabolite M-II, suvorexant, and
lemborexant in human plasma and breast milk to accumulate information on the safety and transfer of MRAs and DORAs into breast milk. Samples of MRAs (ramelteon and M-II) in plasma and breast milk were prepared using liquid-liquid extraction (LLE) with ethyl acetate. For DORAs (suvorexant and
lemborexant), LLE with ethyl acetate was applied to plasma samples. For breast milk samples, significant ion suppression was observed for LLE with ethyl acetate. Solid-phase extraction (SPE) cartridges capable of removing phospholipids improved the matrix effects. Finally, protein precipitation with methanol and an SPE cartridge, InertSep® Phospholipid Remover, were selected for breast milk sample preparation. An ACQUITY UPLC BEH C18 column was used for analyte separation. MRAs and DORAs were eluted using isocratic and gradient elution, respectively, and analyzed using electrospray ionization in the positive mode with multiple reaction monitoring. The range of calibration curve for MRAs and DORAs was 0.1-25 and 0.5-50 ng/ml, respectively. Both the plasma and breast milk samples exhibited good linearity over this range. The method was validated by evaluating its accuracy and precision, matrix effect, recovery, carry-over, stability, and dilution integrity. The validated method was successfully applied to clinical samples donated by breastfeeding women and the milk/plasma (M/P) ratio and relative infant dose (RID) of
lemborexant (one case) and suvorexant (two cases) were estimated. The M/P ratio of
lemborexant was <1, and the RID was 1.05 %. The M/P ratio of suvorexant was <0.1, and RID was 0.11-0.20 %. This method will be useful for future studies evaluating the safety of these drugs during breastfeeding.