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

Diphenhydramine, a sedative histamine H1-receptor(H1R) antagonist, was evaluated as a probe to measure drug/H+- antiporterfunction at the blood–brain barrier. In situ brain perfusion experiments in mice and rats showed that diphenhydraminetransport at the blood–brain barrierwas saturable, following Michaelis–Menten kineticswith 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 diphenhydramineinflux while passive diffusion accounted for only 23%. [14C] Diphenhydramine blood–brain barriertransport was proton and clonidinesensitive 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] diphenhydraminewere measured by positron emission tomography imaging in rats. [11C] Diphenhydraminekinetics in different brain regions were not influenced by displacement with 1 mg kg−1 unlabeled d...