Computational modelling of paracellular diffusion and OCT3 mediated transport of metformin in the perfused human placenta
Computational modelling of paracellular diffusion and OCT3 mediated transport of metformin in the perfused human placenta
Metformin is an antidiabetic drug, increasingly prescribed in pregnancy and has been shown to cross the human placenta. The mechanisms underlying placental metformin transfer remain unclear. This study investigated the roles of drug transporters and paracellular diffusion in the bidirectional transfer of metformin across the human placental syncytiotrophoblast using placental perfusion experiments and computational modelling. 14C-metformin transfer was observed in the maternal to fetal and fetal to maternal directions and was not competitively inhibited by 5 mM unlabelled metformin. Computational modelling of the data was consistent with overall placental transfer via paracellular diffusion. Interestingly, the model also predicted a transient peak in fetal 14C-metformin release due to trans-stimulation of OCT3 by unlabelled metformin at the basal membrane. To test this hypothesis a second experiment was designed. OCT3 substrates (5 mM metformin, 5 mM verapamil and 10 mM decynium-22) added to the fetal artery trans-stimulated release of 14C-metformin from the placenta into the fetal circulation, while 5 mM corticosterone did not. This study demonstrated activity of OCT3 transporters on the basal membrane of the human syncytiotrophoblast. However, we did not detect a contribution of either OCT3 or apical membrane transporters to overall materno-fetal transfer, which could be represented adequately by paracellular diffusion in our system.
Mathematical model(s), Organic cation transporter(s) (OCT), Paracellular transport, Placenta
2570-2580
Lofthouse, Emma M.
abbdd7f0-65c6-4f18-b86c-3306f963b29f
Cleal, Jane
18cfd2c1-bd86-4a13-b38f-c321af56da66
Lewis, Rohan M.
caaeb97d-ea69-4f7b-8adb-5fa25e2d3502
Sengers, Bram G.
d6b771b1-4ede-48c5-9644-fa86503941aa
15 August 2023
Lofthouse, Emma M.
abbdd7f0-65c6-4f18-b86c-3306f963b29f
Cleal, Jane
18cfd2c1-bd86-4a13-b38f-c321af56da66
Lewis, Rohan M.
caaeb97d-ea69-4f7b-8adb-5fa25e2d3502
Sengers, Bram G.
d6b771b1-4ede-48c5-9644-fa86503941aa
Lofthouse, Emma M., Cleal, Jane, Lewis, Rohan M. and Sengers, Bram G.
(2023)
Computational modelling of paracellular diffusion and OCT3 mediated transport of metformin in the perfused human placenta.
Journal of Pharmaceutical Sciences, 112 (9), .
(doi:10.1016/j.xphs.2023.05.008).
Abstract
Metformin is an antidiabetic drug, increasingly prescribed in pregnancy and has been shown to cross the human placenta. The mechanisms underlying placental metformin transfer remain unclear. This study investigated the roles of drug transporters and paracellular diffusion in the bidirectional transfer of metformin across the human placental syncytiotrophoblast using placental perfusion experiments and computational modelling. 14C-metformin transfer was observed in the maternal to fetal and fetal to maternal directions and was not competitively inhibited by 5 mM unlabelled metformin. Computational modelling of the data was consistent with overall placental transfer via paracellular diffusion. Interestingly, the model also predicted a transient peak in fetal 14C-metformin release due to trans-stimulation of OCT3 by unlabelled metformin at the basal membrane. To test this hypothesis a second experiment was designed. OCT3 substrates (5 mM metformin, 5 mM verapamil and 10 mM decynium-22) added to the fetal artery trans-stimulated release of 14C-metformin from the placenta into the fetal circulation, while 5 mM corticosterone did not. This study demonstrated activity of OCT3 transporters on the basal membrane of the human syncytiotrophoblast. However, we did not detect a contribution of either OCT3 or apical membrane transporters to overall materno-fetal transfer, which could be represented adequately by paracellular diffusion in our system.
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Accepted/In Press date: 15 May 2023
e-pub ahead of print date: 19 May 2023
Published date: 15 August 2023
Additional Information:
Funding Information:
This work was funded by the BBSRC [BB/R002762/1]. We would like to thank the NIHR funded research nurse team and midwives at the Princess Anne Hospital for their assistance in collecting placentas.
Keywords:
Mathematical model(s), Organic cation transporter(s) (OCT), Paracellular transport, Placenta
Identifiers
Local EPrints ID: 477423
URI: http://eprints.soton.ac.uk/id/eprint/477423
ISSN: 0022-3549
PURE UUID: 3d56bcfb-f169-46bc-9ee1-b443da3cfe45
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Date deposited: 06 Jun 2023 16:55
Last modified: 17 Mar 2024 03:06
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Author:
Emma M. Lofthouse
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