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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
Glibenclamide transfer across the perfused human placenta is determined by albumin binding not transporter activity
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 modelling. 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 modelling 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 modelling.
OATP and ABC transporters, albumin, glibenclamide, human placenta
0928-0987
Lofthouse, Emma
abbdd7f0-65c6-4f18-b86c-3306f963b29f
Cleal, Jane
18cfd2c1-bd86-4a13-b38f-c321af56da66
Hudson, Georgina J
abe4bf8c-6ae0-4148-873e-484ed31d1b9e
Lewis, Rohan
caaeb97d-ea69-4f7b-8adb-5fa25e2d3502
Sengers, Bram
d6b771b1-4ede-48c5-9644-fa86503941aa
Lofthouse, Emma
abbdd7f0-65c6-4f18-b86c-3306f963b29f
Cleal, Jane
18cfd2c1-bd86-4a13-b38f-c321af56da66
Hudson, Georgina J
abe4bf8c-6ae0-4148-873e-484ed31d1b9e
Lewis, Rohan
caaeb97d-ea69-4f7b-8adb-5fa25e2d3502
Sengers, Bram
d6b771b1-4ede-48c5-9644-fa86503941aa

Lofthouse, Emma, Cleal, Jane, Hudson, Georgina J, Lewis, Rohan and Sengers, Bram (2020) Glibenclamide transfer across the perfused human placenta is determined by albumin binding not transporter activity. European Journal of Pharmaceutical Sciences, 152, [105436]. (doi:10.1016/j.ejps.2020.105436).

Record type: Article

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 modelling. 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 modelling 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 modelling.

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Accepted/In Press date: 23 June 2020
e-pub ahead of print date: 24 June 2020
Keywords: OATP and ABC transporters, albumin, glibenclamide, human placenta

Identifiers

Local EPrints ID: 442058
URI: http://eprints.soton.ac.uk/id/eprint/442058
ISSN: 0928-0987
PURE UUID: a5b37dbc-c507-4b45-bbd9-ab47a269a248
ORCID for Jane Cleal: ORCID iD orcid.org/0000-0001-7978-4327
ORCID for Rohan Lewis: ORCID iD orcid.org/0000-0003-4044-9104
ORCID for Bram Sengers: ORCID iD orcid.org/0000-0001-5859-6984

Catalogue record

Date deposited: 06 Jul 2020 16:31
Last modified: 26 Nov 2021 06:16

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Contributors

Author: Emma Lofthouse
Author: Jane Cleal ORCID iD
Author: Georgina J Hudson
Author: Rohan Lewis ORCID iD
Author: Bram Sengers ORCID iD

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