title: Diphenhydramine as a selective probe to study H+-antiporter function at the blood-brain barrier: Application to [11C]diphenhydramine positron emission tomography imaging.
abstract: Diphenhydramine, a sedative histamine H1-receptor (H1R) antagonist, was evaluated as a probe to measure drug/H+-antiporter function at the blood-brain barrier. In situ brain perfusion experiments in mice and rats showed that diphenhydramine transport at the blood-brain barrier was saturable, following Michaelis-Menten kinetics with a Km= 2.99 mM and Vmax= 179.5 nmol s-1g-1. In the pharmacological plasma concentration range the carrier-mediated component accounted for 77% of diphenhydramine influx while passive diffusion accounted for only 23%. [14C]Diphenhydramine blood-brain barrier transport was proton and clonidine sensitive but was influenced by neither tetraethylammonium, a MATE1 (SLC47A1), and OCT/OCTN (SLC22A1-5) modulator, nor P-gp/Bcrp (ABCB1a/1b/ABCG2) deficiency. Brain and plasma kinetics of [11C]diphenhydramine were measured by positron emission tomography imaging in rats. [11C]Diphenhydramine kinetics in different brain regions were not influenced by displacement with 1 mg kg-1unlabeled diphenhydramine, indicating the specificity of the brain positron emission tomography signal for blood-brain barrier transport activity over binding to any central nervous system target in vivo. [11C]Diphenhydramine radiometabolites were not detected in the brain 15 min after injection, allowing for the reliable calculation of [11C]diphenhydramine brain uptake clearance (Clup= 0.99 ± 0.18 mL min-1cm-3). Diphenhydramine is a selective and specific H+-antiporter substrate. [11C]Diphenhydramine positron emission tomography imaging offers a reliable and noninvasive method to evaluate H+-antiporter function at the blood-brain barrier.
authors.affiliation: 1 Imagerie Moléculaire In Vivo, IMIV, CEA, Inserm, CNRS, Univ. Paris-Sud, Université Paris Saclay, CEA-SHFJ, Orsay, France.|2 Variabilité de réponse aux psychotropes, INSERM, U1144, Paris, France; Université Paris Descartes, Faculté de pharmacie, UMR-S 1144, Paris, F-75006, France. Université Paris Diderot, UMR-S 1144, Paris, F-75013, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Auvity
authors.affiliation: 2 Variabilité de réponse aux psychotropes, INSERM, U1144, Paris, France; Université Paris Descartes, Faculté de pharmacie, UMR-S 1144, Paris, F-75006, France. Université Paris Diderot, UMR-S 1144, Paris, F-75013, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Chapy
authors.affiliation: 1 Imagerie Moléculaire In Vivo, IMIV, CEA, Inserm, CNRS, Univ. Paris-Sud, Université Paris Saclay, CEA-SHFJ, Orsay, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Goutal
authors.affiliation: 1 Imagerie Moléculaire In Vivo, IMIV, CEA, Inserm, CNRS, Univ. Paris-Sud, Université Paris Saclay, CEA-SHFJ, Orsay, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Caillé
authors.affiliation: 2 Variabilité de réponse aux psychotropes, INSERM, U1144, Paris, France; Université Paris Descartes, Faculté de pharmacie, UMR-S 1144, Paris, F-75006, France. Université Paris Diderot, UMR-S 1144, Paris, F-75013, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Hosten
authors.affiliation: 2 Variabilité de réponse aux psychotropes, INSERM, U1144, Paris, France; Université Paris Descartes, Faculté de pharmacie, UMR-S 1144, Paris, F-75006, France. Université Paris Diderot, UMR-S 1144, Paris, F-75013, France.
authors.forename: Maria
authors.initials: M
authors.lastname: Smirnova
authors.affiliation: 2 Variabilité de réponse aux psychotropes, INSERM, U1144, Paris, France; Université Paris Descartes, Faculté de pharmacie, UMR-S 1144, Paris, F-75006, France. Université Paris Diderot, UMR-S 1144, Paris, F-75013, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Declèves
authors.affiliation: 1 Imagerie Moléculaire In Vivo, IMIV, CEA, Inserm, CNRS, Univ. Paris-Sud, Université Paris Saclay, CEA-SHFJ, Orsay, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Tournier
authors.affiliation: 1 Imagerie Moléculaire In Vivo, IMIV, CEA, Inserm, CNRS, Univ. Paris-Sud, Université Paris Saclay, CEA-SHFJ, Orsay, France.|2 Variabilité de réponse aux psychotropes, INSERM, U1144, Paris, France; Université Paris Descartes, Faculté de pharmacie, UMR-S 1144, Paris, F-75006, France. Université Paris Diderot, UMR-S 1144, Paris, F-75013, France.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cisternino
mesh_terms: D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002250:Carbon Radioisotopes; D004155:Diphenhydramine / Q000097:blood / Q000493:pharmacokinetics*; D007700:Kinetics; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods*; D017494:Proton Pumps / Q000378:metabolism*; D017207:Rats, Sprague-Dawley
chemical_list: D002250:Carbon Radioisotopes; D017494:Proton Pumps; D004155:Diphenhydramine
keywords: Biological transporter; blood–brain barrier; positron emission tomography; proton antiporter; solute carrier