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

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.

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