Division of Obstetrics and Feto-Maternal Medicine, Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria.
Reproductive Biology Unit, Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria.
Biol Reprod. 2020 Jun 23;103(1):135-143. doi: 10.1093/biolre/ioaa048.
The use of drugs in pregnancy always raises concerns regarding potential fetal exposure and possible adverse effects through their accumulation in fetal tissues and organs. Barusiban is an oxytocin antagonist under development for potential use as tocolytic in preterm-labor patients. It displays greater affinity for the oxytocin receptor compared to vasopressin V1A receptor and would thus not interfere with vasopressin-induced effects of the V1A receptor. Barusiban placental transfer was determined in the rabbit and cynomolgus monkey and in an ex vivo human cotyledon model. In the rabbit, there was an approximately 5% transfer of barusiban from the maternal to the fetal blood, without significant accumulation in any of the investigated fetal tissues. In the cynomolgus monkeys, the mean fetal plasma barusiban concentration was 9.1% of the maternal level. This was similar to the percentage of barusiban transfer in the human placental single cotyledon, which once equilibrated ranged between 9.3 and 11.0% over the observation period. The transfer of the small-molecule antipyrine as a comparator in this human model was approximately three times greater. The similarity in the degree of transfer in the cynomolgus monkey and human cotyledon, while being less in the rabbit, may reflect the species-specific placental barrier structure between the maternal and fetal compartments. In conclusion, limited placental transfer of barusiban occurred in all three models. The similarity of barusiban transfer in the cynomolgus and the human placental single cotyledon suggests the latter ex vivo model to be useful in assessing future drug candidates to be used in pregnant women.
在妊娠期间使用药物时，人们总是会担心药物可能会透过胎盘进入胎儿体内，并在胎儿组织和器官中蓄积，从而对胎儿产生潜在的不良影响。巴鲁昔班是一种正在开发中的催产素拮抗剂，有望作为早产患者的宫缩抑制剂使用。与血管加压素 V1A 受体相比，它对催产素受体具有更高的亲和力，因此不会干扰血管加压素对 V1A 受体的作用。本研究旨在检测巴鲁昔班在兔和食蟹猴以及离体人胎盘模型中的胎盘转运情况。在兔中，巴鲁昔班约有 5%从母体转移至胎儿血液中，且在任何研究的胎儿组织中均无明显蓄积。在食蟹猴中，母猴的平均胎儿血浆巴鲁昔班浓度为母体水平的 9.1%。这与离体人胎盘单叶模型中观察到的巴鲁昔班转移百分比相似，在平衡期内，该模型中巴鲁昔班的转移百分比在观察期间的 9.3%至 11.0%之间。作为比较，小分子安替比林在该人模型中的转移百分比约为巴鲁昔班的三倍。在猴和人胎盘单叶模型中，巴鲁昔班的转移程度相似，而在兔中则较低，这可能反映了母体和胎儿隔室之间特定于物种的胎盘屏障结构。总之，在所有三种模型中，巴鲁昔班的胎盘转移程度都较低。食蟹猴和人胎盘单叶模型中巴鲁昔班的转移相似性表明，后者的离体模型可用于评估未来用于孕妇的候选药物。
