title: Effects of selected OATP and/or ABC transporter inhibitors on the brain and whole-body distribution of glyburide.
abstract: Glyburide (glibenclamide, GLB) is a widely prescribed antidiabetic with potential beneficial effects in central nervous system injury and diseases. In vitro studies show that GLB is a substrate of organic anion transporting polypeptide (OATP) and ATP-binding cassette (ABC) transporter families, which may influence GLB distribution and pharmacokinetics in vivo. In the present study, we used [(11)C]GLB positron emission tomography (PET) imaging to non-invasively observe the distribution of GLB at a non-saturating tracer dose in baboons. The role of OATP and P-glycoprotein (P-gp) in [(11)C]GLB whole-body distribution, plasma kinetics, and metabolism was assessed using the OATP inhibitor rifampicin and the dual OATP/P-gp inhibitor cyclosporine. Finally, we used in situ brain perfusion in mice to pinpoint the effect of ABC transporters on GLB transport at the blood-brain barrier (BBB). PET revealed the critical role of OATP on liver [(11)C]GLB uptake and its subsequent impact on [(11)C]GLB metabolism and plasma clearance. OATP-mediated uptake also occurred in the myocardium and kidney parenchyma but not the brain. The inhibition of P-gp in addition to OATP did not further influence [(11)C]GLB tissue and plasma kinetics. At the BBB, the inhibition of both P-gp and breast cancer resistance protein (BCRP) was necessary to demonstrate the role of ABC transporters in limiting GLB brain uptake. This study demonstrates that GLB distribution, metabolism, and elimination are greatly dependent on OATP activity, the first step in GLB hepatic clearance. Conversely, P-gp, BCRP, and probably multidrug resistance protein 4 work in synergy to limit GLB brain uptake.
authors.affiliation: CEA, DSV, I2BM, Service Hospitalier Frédéric Joliot, Orsay, 91401, France, nicolas.tournier@cea.fr.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Tournier
authors.forename: Wadad
authors.initials: W
authors.lastname: Saba
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cisternino
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Peyronneau
authors.forename: Annelaure
authors.initials: A
authors.lastname: Damont
authors.forename: Sébastien
authors.initials: S
authors.lastname: Goutal
authors.forename: Albertine
authors.initials: A
authors.lastname: Dubois
authors.forename: Frédéric
authors.initials: F
authors.lastname: Dollé
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Scherrmann
authors.forename: Héric
authors.initials: H
authors.lastname: Valette
authors.forename: Bertrand
authors.initials: B
authors.lastname: Kuhnast
authors.forename: Michel
authors.initials: M
authors.lastname: Bottlaender
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000166:Acridines / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004285:Dogs; D005905:Glyburide / Q000378:metabolism* / Q000494:pharmacology; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D048530:Papio anubis; D044005:Tetrahydroisoquinolines / Q000378:metabolism / Q000494:pharmacology
chemical_list: D018528:ATP-Binding Cassette Transporters; D000166:Acridines; D027361:Organic Anion Transporters; D044005:Tetrahydroisoquinolines; C083501:Elacridar; D005905:Glyburide
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