Glibenclamide transfer across the perfused human placenta is determined by albumin binding not transporter activity.
Glibenclamide transfer across the perfused human placenta is determined by albumin binding not transporter activity.
复制标题
格列本脲跨灌注人胎盘的转移是由白蛋白结合而不是转运蛋白活性决定的。
DOI：
10.1016/j.ejps.2020.105436
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Lofthouse EM
中科院分区：
文献类型：
--
作者：
Lofthouse EM
胎盘介导母体营养物质转移到胎儿循环中，同时清除可能对胎儿发育有害的胎儿废物，药物和环境毒素。本研究使用胎盘灌注实验和计算模型研究了药物转运蛋白和蛋白结合在抗糖尿病药物格列本脲通过人胎盘合胞体滋养层转移中的作用。在不存在白蛋白的情况下，胎盘从胎仔循环中摄取格列本脲不受溴磺酞（BSP）竞争性抑制的影响，表明OATP 2B 1不介导胎盘从胎仔中摄取格列本脲。在存在母体和胎仔白蛋白的情况下，BSP通过从BSA中置换格列本脲，增加驱动扩散转运的格列本脲游离分数，从而增加胎盘从胎仔循环中摄取格列本脲。P-gp和BCRP抑制剂GF 120918不影响胎盘从母体循环中摄取格列本脲，因此本研究未发现任何证据表明胎盘格列本脲转移中存在顶端外排转运蛋白。计算建模证实，白蛋白结合而非转运蛋白活性是格列本脲通过人胎盘转移的主要因素。BSP与白蛋白结合对促进格列本脲扩散转移的影响突出了药物-蛋白结合相互作用及其使用计算建模解释的重要性。
The placenta mediates the transfer of maternal nutrients into the fetal circulation while removing fetal waste products, drugs and environmental toxins that may otherwise be detrimental to fetal development. This study investigated the role of drug transporters and protein binding in the transfer of the antidiabetic drug glibenclamide across the human placental syncytiotrophoblast using placental perfusion experiments and computational modeling. In the absence of albumin, placental glibenclamide uptake from the fetal circulation was not affected by competitive inhibition with bromosulphothalein (BSP), indicating that OATP2B1 does not mediate placental glibenclamide uptake from the fetus. In the presence of maternal and fetal albumin, BSP increased placental glibenclamide uptake from the fetal circulation by displacing glibenclamide from BSA, increasing the free fraction of glibenclamide driving diffusive transport. The P-gp and BCRP inhibitor GF120918 did not affect placental glibenclamide uptake from the maternal circulation and as such this study did not find any evidence for the apical efflux transporters in placental glibenclamide transfer. Computational modeling confirmed that albumin binding and not transporter activity, is the dominant factor in the transfer of glibenclamide across the human placenta. The effect of BSP binding to albumin on promoting the diffusive transfer of glibenclamide highlights the importance of drug-protein binding interactions and their interpretation using computational modeling.
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DOI：
10.1152/ajpregu.2000.279.4.r1495
发表时间：
2000-10-01
影响因子：
2.8
作者：
St-Pierre, MV;Serrano, MA;Marin, JJG
通讯作者：
Marin, JJG
影响因子：
7.2
作者：
Schwartz, Rachelle A.;Rosenn, Barak;Koren, Gideon
通讯作者：
Koren, Gideon
胎盘代谢对脂肪酸向胎儿转运的影响[S]
影响因子：
6.5
作者：
Simone Perazzolo;B. Hirschmugl;C. Wadsack;G. Desoye;Rohan M. Lewis;B. Sengers
通讯作者：
B. Sengers
研究多药耐药蛋白（MRP）转运蛋白在人胎盘中胎儿至母体格列本脲外流中的潜在作用
影响因子：
1.6
作者：
C. Gedeon;G. Anger;A. Lubetsky;M. P. Miller;Gideon Koren
通讯作者：
Gideon Koren
影响因子：
3.3
作者：
CROOKS, MJ;BROWN, KF
通讯作者：
BROWN, KF