Glibenclamide transfer across the perfused human placenta is determined by albumin binding not transporter activity

Abstract

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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