Perfusion studies of glyburide transfer across the human placenta: Implications for fetal safety
Perfusion studies of glyburide transfer across the human placenta: Implications for fetal safety
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DOI：
10.1016/j.ajog.2005.12.005
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发表时间：
2006-07-01
影响因子：
9.8
通讯作者：
Koren, Gideon
中科院分区：
文献类型：
--
作者：
Kraemer, Jennifer;Klein, Julia;Koren, Gideon
目的：糖尿病影响高达5%的妇女。口服降糖药已被避免，因为假设他们的胎盘转移可能会导致胎儿-新生儿低血糖。最近的一项随机试验无法显示脐带血中可测量的格列本脲水平，尽管母亲使用常规剂量的格列本脲治疗。这种现象背后的机制尚不清楚。我们的研究的目的是记录，使用人胎盘灌注模型，是否格列本脲是积极effluxed从胎儿到母体circulation.Study设计：在体外灌注研究人子叶进行定量胎盘转移格列本脲。使用闭环实验并将格列本脲以200 ng/mL引入母体和胎儿循环，我们寻找从胎儿到母体的逆浓度梯度转运的证据。在平行实验中，P-糖蛋白抑制剂维拉帕米被用来试图抑制transplacental glyburide movement.Results：有非常显着的传输glyburide对浓度梯度从胎儿到母体循环。实验期开始时胎儿与母体浓度比为0.92 +/- 0.23，3小时后为0.31 +/- 0.47（P = .01）（n = 5）。维拉帕米没有修改格列本脲transport.Conclusion：这是第一个直接的证据，积极格列本脲运输从胎儿到母亲，在一般情况下，在怀孕期间使用的任何药物。这些实验表明，格列本脲是主动外排的转运蛋白以外的P-糖蛋白。另一种可能是，少数格列本脲由P-糖蛋白携带，但大部分胎儿负荷通过尚未鉴定的胎盘转运系统泵送至母体。(c)2006 Mosby，Inc. All rights reserved.
Objective: Gestational diabetes affects up to 5% of women. Oral hypoglycemics have been avoided because of the assumption that their placental transfer may cause fetal-neonatal hypoglycemia. A recent randomized trial could not show measurable glyburide levels in umbilical blood despite maternal treatment with regular doses of glyburide. The mechanism underlying this phenomenon is not known. The objective of our study was to document, using a human placenta perfusion model, whether glyburide is actively effluxed from the fetal to the maternal circulation.Study design: In vitro perfusion studies of human cotyledon were performed to quantify placental transfer of glyburide. Using close circle experiments and introducing glyburide to both maternal and fetal circulations at 200 ng/mL, we looked for evidence of transport against concentration gradient from the fetus to the mother. In parallel experiments, the P-glycoprotein inhibitor verapamil was used in an attempt to inhibit transplacental glyburide movement.Results: There was highly significant transfer of glyburide against concentration gradient from the fetal to the maternal circulation. Fetal-to-maternal concentration ratio was 0.92 +/- 0.23 at the start of the experimental period and 0.31 +/- 0.47 3 hours later (P = .01) (n = 5). Verapamil did not modify glyburide transport.Conclusion: This is the first direct evidence of active glyburide transport from the fetus to the mother and, in general, of any medicinal drug used during pregnancy. These experiments suggest that glyburide is actively efflux by a transporter other than P-glycoprotein. Alternatively, it is possible that a minority of glyburide is carried by P-glycoprotein, but most of the fetal load is pumped to the mother by a yet-unidentified placental transport system. (c) 2006 Mosby, Inc. All rights reserved.