Diphenhydramine as a selective probe to study H+-antiporter function at the blood–brain barrier: Application to [11C]diphenhydramine positron emission tomography imaging. Issue 6 (June 2017)

• Record Type: Journal Article
• Authors: Auvity, Sylvain; Chapy, Hélène; Goutal, Sébastien; Caillé, Fabien; Hosten, Benoit; Smirnova, Maria; Declèves, Xavier; Tournier, Nicolas; Cisternino, Salvatore
• Is Part Of: Journal of cerebral blood flow & metabolism. Volume 37:Issue 6(2017)
• Page Start: 2185
• Page End: 2195
• Publication Date: 2017-06
• Subjects: Biological transporter -- blood–brain barrier -- proton antiporter -- positron emission tomography -- solute carrier; Cerebral circulation -- Periodicals; Brain -- Metabolism -- Periodicals; Brain -- Blood-vessels -- Periodicals; Cerebrovascular disease -- Periodicals; 612.824
• DOI: 10.1177/0271678X16662042
• Languages: English
• ISSNs: 0271-678X

Abstract

Diphenhydramine, a sedative histamine H1 -receptor (H1 R) 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 −1 g −1 . In the pharmacological plasma concentration range the carrier-mediated component accounted for 77% of diphenhydramine influx while passive diffusion accounted for only 23%. [ 14 C]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 [ 11 C]diphenhydramine were measured by positron emission tomography imaging in rats. [ 11 C]Diphenhydramine kinetics in different brain regions were not influenced by displacement with 1 mg kg −1 unlabeled 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. [ 11 C]Diphenhydramine radiometabolites were not detected in the brain 15 min after injection, allowing for the reliable calculation of [ 11 C]diphenhydramine brain uptake clearance (Clup = 0.99 ± 0.18 mL min −1 cm −3 ). Diphenhydramine is a selective and specific H + -antiporter substrate. [ 11 C]Diphenhydramine positron emission tomography imaging offers a reliable and noninvasive method to evaluate H + -antiporter function at the blood–brain barrier.