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Interplay of drug transporters P-glycoprotein (MDR1), MRP1, OATP1A2 and OATP1B3 in passage of maraviroc across human placenta

Tupova, L. and Hirschmugl, B. and Sucha, S. and Pilarova, V. and Székely, V. and Bakos, Éva and Özvegy-Laczka, Csilla (2020) Interplay of drug transporters P-glycoprotein (MDR1), MRP1, OATP1A2 and OATP1B3 in passage of maraviroc across human placenta. BIOMEDICINE AND PHARMACOTHERAPY, 129. ISSN 0753-3322

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Abstract

Special attention is required when pharmacological treatment is indicated for a pregnant woman. P-glycoprotein (MDR1) is a well-known transporter localized in the maternal blood-facing apical membrane of placental syncytiotrophoblast and is considered to play an important role in protecting the developing fetus. Maraviroc, a MDR1 substrate that is registered for treatment of HIV infection, shows a low toxicity profile, suggesting favorable tolerability also if administered to pregnant women. Nevertheless, there is only poor understanding to date regarding the extent to which it permeates across the placental barrier and what are the transport mechanisms involved. Endeavoring to clarify the passage of maraviroc across placenta, we used in this study the method of closed-circuit perfusion of maraviroc across human placental cotyledon. The data obtained confirmed slight involvement of MDR1, but they also suggest possible interaction with other transport system(s) working in the opposite direction from that of MDR1. Complementary in vitro studies, including cellular experiments on choriocarcinoma BeWo cells as well as transporter-overexpressing MDCKII and A431 cell lines and accumulation in placental fresh villous fragments, revealed maraviroc transport by MRP1, OATP1A2, and OATP1B3 transporters. Based on mRNA expression data in the placental tissue, isolated trophoblasts, and fetal endothelial cells, especially MRP1 and OATP1A2 seem to play a crucial role in cooperatively driving maraviroc into placental tissue. By the example of maraviroc, we show here the important interplay of transporters in placental drug handling and its possibility to overcome the MDR1-mediated efflux. © 2020 The Authors

Item Type: Article
Additional Information: Charles University, Faculty of Pharmacy in Hradec Kralove, Department of Pharmacology and Toxicology, Akademika Heyrovskeho 1203, Hradec Kralove, Czech Republic Medical University of Graz, Department of Obstetrics and Gynecology, Graz, 8036, Austria Charles University, Faculty of Pharmacy in Hradec Kralove, Department of Analytical Chemistry, Akademika Heyrovskeho 1203, Hradec Kralove, Czech Republic Membrane Protein Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Magyar tudósok krt. 2., Budapest, H-1117, Hungary Export Date: 23 July 2020 CODEN: BIPHE Correspondence Address: Ceckova, M.; Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203, Czech Republic; email: martina.ceckova@faf.cuni.cz Funding details: 616216/C/2016 Funding details: Magyar Tudományos Akadémia, MTA Funding details: Univerzita Karlova v Praze, UK, PRIMUS/20/MED/010, SVV 260 549 Funding details: Hungarian Scientific Research Fund, OTKA, FK 128751 Funding text 1: This study was supported by the Charles University ( PRIMUS/20/MED/010 and SVV 260 549 ), the Grant Agency of the Charles University GAUK ( 616216/C/2016 ), and by EFSA-CDN (No. CZ.02.1.01/0.0/0.0/16_019/0000841 ) co-funded by ERDF. Lenka Tupova is the holder of Martina Roeselova Memorial Fellowships 2019 and Csilla Özvegy-Laczka received grant support from the National Research, Development and Innovation Office (OTKA, grant number FK 128751 ) and the János Bolyai fellowship of the Hungarian Academy of Sciences . Charles University, Faculty of Pharmacy in Hradec Kralove, Department of Pharmacology and Toxicology, Akademika Heyrovskeho 1203, Hradec Kralove, Czech Republic Medical University of Graz, Department of Obstetrics and Gynecology, Graz, 8036, Austria Charles University, Faculty of Pharmacy in Hradec Kralove, Department of Analytical Chemistry, Akademika Heyrovskeho 1203, Hradec Kralove, Czech Republic Membrane Protein Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Magyar tudósok krt. 2., Budapest, H-1117, Hungary Export Date: 11 August 2020 CODEN: BIPHE Correspondence Address: Ceckova, M.; Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203, Czech Republic; email: martina.ceckova@faf.cuni.cz Chemicals/CAS: ABC transporter subfamily B, 149200-37-3, 208997-77-7; carnitine, 461-06-3, 541-15-1, 56-99-5; elacridar, 143664-11-3; maraviroc, 376348-65-1; multidrug resistance associated protein 1; ritonavir, 155213-67-5; salazosulfapyridine, 599-79-1; verapamil, 152-11-4, 52-53-9; verlukast, 115104-28-4 Tradenames: mk 571, MedChemexpress, United States Manufacturers: MedChemexpress, United States; Moravek, United States; nih aids reagent program Funding details: 616216/C/2016 Funding details: Magyar Tudományos Akadémia, MTA Funding details: Univerzita Karlova v Praze, UK, PRIMUS/20/MED/010, SVV 260 549 Funding details: Hungarian Scientific Research Fund, OTKA, FK 128751 Funding text 1: This study was supported by the Charles University ( PRIMUS/20/MED/010 and SVV 260 549 ), the Grant Agency of the Charles University GAUK ( 616216/C/2016 ), and by EFSA-CDN (No. CZ.02.1.01/0.0/0.0/16_019/0000841 ) co-funded by ERDF. Lenka Tupova is the holder of Martina Roeselova Memorial Fellowships 2019 and Csilla Özvegy-Laczka received grant support from the National Research, Development and Innovation Office (OTKA, grant number FK 128751 ) and the János Bolyai fellowship of the Hungarian Academy of Sciences .
Uncontrolled Keywords: placenta; DRUG TRANSPORTERS; OATP; Drug–drug interactions; MRP1; Maraviroc;
Subjects: Q Science / természettudomány > QD Chemistry / kémia > QD01 Analytical chemistry / analitikai kémia
R Medicine / orvostudomány > RG Gynecology and obstetrics / nőgyógyászat, szülészet
R Medicine / orvostudomány > RM Therapeutics. Pharmacology / terápia, gyógyszertan
SWORD Depositor: MTMT SWORD
Depositing User: MTMT SWORD
Date Deposited: 11 Aug 2020 15:38
Last Modified: 16 Sep 2020 12:24
URI: http://real.mtak.hu/id/eprint/112080

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