Abstract：
OBJECTIVE: In the absence of safety data in humans, the use of cannabidiol (CBD) is not recommended during pregnancy. Yet >50% of pregnancies in women with epilepsy are unintended, making fetal exposure to CBD possible. As a small-molecule, highly lipid-soluble drug, CBD is likely to be distributed into the placenta and cross it. To estimate the placental distribution profile of CBD and its potential short-term placental effects, we conducted an ex vivo perfusion study in human placentas.
METHODS: Placentas were obtained from healthy women undergoing cesarean deliveries. Selected cotyledons were cannulated and perfused for 180 min with a CBD-containing medium (250 ng/mL, .796 μmol·L-1 ; representative of a low therapeutic concentration; n = 8). CBD concentrations were determined at 180 min in the medium and placental tissue using liquid chromatography-tandem mass spectrometry. A customized gene panel array was used to analyze the expression of selected genes in the perfused placental cotyledons as well as in placentas perfused with 1000 ng/mL CBD (3.18 μmol·L-1 ; high therapeutic concentration; n = 8) and in those exposed to the vehicle.
RESULTS: CBD was sequestered in the placental tissue, exhibiting significant variability across samples (median = 5342 ng/g tissue, range = 1066-9351 ng/g tissue). CBD concentrations in the fetal compartment were one fifth of those measured in the maternal compartment (median = 59 ng/mL, range = 48-72 ng/mL vs. 280 = ng/mL, range = 159-388 ng/mL, respectively; p < .01). Placental gene expression was not significantly altered by CBD.
CONCLUSIONS: The placenta acts as a depot compartment for CBD, slowing down its distribution to the fetus. This phenomenon might yield flatter but prolonged fetal CBD levels in vivo. The attenuated transplacental CBD transfer does not imply that its use by pregnant women is safe for the fetus. Only pregnancy registries and neurocognitive assessments would establish the risk of being antenatally exposed to CBD.
METHODS: Placentas were obtained from healthy women undergoing cesarean deliveries. Selected cotyledons were cannulated and perfused for 180 min with a CBD-containing medium (250 ng/mL, .796 μmol·L-1 ; representative of a low therapeutic concentration; n = 8). CBD concentrations were determined at 180 min in the medium and placental tissue using liquid chromatography-tandem mass spectrometry. A customized gene panel array was used to analyze the expression of selected genes in the perfused placental cotyledons as well as in placentas perfused with 1000 ng/mL CBD (3.18 μmol·L-1 ; high therapeutic concentration; n = 8) and in those exposed to the vehicle.
RESULTS: CBD was sequestered in the placental tissue, exhibiting significant variability across samples (median = 5342 ng/g tissue, range = 1066-9351 ng/g tissue). CBD concentrations in the fetal compartment were one fifth of those measured in the maternal compartment (median = 59 ng/mL, range = 48-72 ng/mL vs. 280 = ng/mL, range = 159-388 ng/mL, respectively; p < .01). Placental gene expression was not significantly altered by CBD.
CONCLUSIONS: The placenta acts as a depot compartment for CBD, slowing down its distribution to the fetus. This phenomenon might yield flatter but prolonged fetal CBD levels in vivo. The attenuated transplacental CBD transfer does not imply that its use by pregnant women is safe for the fetus. Only pregnancy registries and neurocognitive assessments would establish the risk of being antenatally exposed to CBD.
摘要：
目的：在缺乏人体安全性数据的情况下，怀孕期间不建议使用大麻二酚（CBD）。然而，癫痫女性中超过50%的怀孕是无意的，使胎儿暴露于CBD成为可能。作为一种小分子,高脂溶性药物，CBD可能会分布到胎盘中并穿过它。为了估计CBD的胎盘分布概况及其潜在的短期胎盘效应，我们在人胎盘中进行了离体灌注研究。
方法：胎盘取自接受剖宫产的健康妇女。将选定的子叶插管并用含CBD的培养基（250ng/mL，0.796μmol/L;代表低治疗浓度;n=8)。使用LC-MS/MS分析在180分钟时测定培养基和胎盘组织中的CBD浓度。使用定制的基因组阵列来分析所选基因在灌注的胎盘子叶以及灌注有1000ng/mLCBD(3.18μmol/L;高治疗浓度;n=8)的胎盘中和暴露于载体的那些中的表达。
结果：CBD在胎盘组织中隔离，在样品中表现出显著的变异性(中位数5,342ng/g组织；范围1,066-9,351ng/g组织)。胎儿隔室中的CBD浓度是母体隔室中测量的浓度的五分之一（中位数59ng/mL；范围48-72ng/mL，vs.280ng/mL,范围159-388ng/mL，分别为；p<0.01)。胎盘基因表达未被CBD显著改变。
结论：胎盘充当CBD的仓库室，减慢其在胎儿中的分布。这种现象可能在体内产生更平坦但延长的胎儿CBD水平。减毒的经胎盘CBD转移并不意味着孕妇使用它对胎儿是安全的。只有怀孕登记和神经认知评估才能确定在产前暴露于CBD的风险。
方法：胎盘取自接受剖宫产的健康妇女。将选定的子叶插管并用含CBD的培养基（250ng/mL，0.796μmol/L;代表低治疗浓度;n=8)。使用LC-MS/MS分析在180分钟时测定培养基和胎盘组织中的CBD浓度。使用定制的基因组阵列来分析所选基因在灌注的胎盘子叶以及灌注有1000ng/mLCBD(3.18μmol/L;高治疗浓度;n=8)的胎盘中和暴露于载体的那些中的表达。
结果：CBD在胎盘组织中隔离，在样品中表现出显著的变异性(中位数5,342ng/g组织；范围1,066-9,351ng/g组织)。胎儿隔室中的CBD浓度是母体隔室中测量的浓度的五分之一（中位数59ng/mL；范围48-72ng/mL，vs.280ng/mL,范围159-388ng/mL，分别为；p<0.01)。胎盘基因表达未被CBD显著改变。
结论：胎盘充当CBD的仓库室，减慢其在胎儿中的分布。这种现象可能在体内产生更平坦但延长的胎儿CBD水平。减毒的经胎盘CBD转移并不意味着孕妇使用它对胎儿是安全的。只有怀孕登记和神经认知评估才能确定在产前暴露于CBD的风险。
