title: Diphenhydramine has similar interspecies net active influx at the blood-brain barrier.
abstract: In rats, oxycodone, diphenhydramine, and [4-chloro-5-fluoro-2-(3-methoxy-2-methyl-phenoxy)-benzyl]-methylamine (CE-157119) undergo net active influx at the blood-brain barrier (BBB) based on significantly greater interstitial fluid compound concentrations (CISF ) than unbound plasma compound concentrations (Cp,u ). Oxycodone and diphenhydramine have CISF :Cp,u of 3.0 and 5.5, respectively, while CE-157119 has an unbound brain compound concentration (Cb,u ):Cp,u of 3.90; Cb,u is a high-confidence CISF surrogate. However, only CE-157119 has published dog and nonhuman primate (nhp) neuropharmacokinetics, which show similar Cb,u :Cp,u (4.61 and 2.04, respectively) as rats. Thus, diphenhydramine underwent identical interspecies neuropharmacokinetics studies to determine if its net active BBB influx in rats replicated in dogs and/or nhp. The single-dose-derived rat Cb,u :Cp,u (3.90) was consistent with prior steady-state-derived CISF :Cp,u and similar to those in dogs (4.88) and nhp (4.51-5.00). All large animal interneurocompartmental ratios were ≤1.8-fold different than their rat values, implying that diphenhydramine has constant and substantial Cb,u -favoring disequilibria in these mammals. Accordingly, the applied Cb,u -forecasting methodology accurately predicted [estimated mean (95% confidence interval) of 0.84 (0.68, 1.05)] Cb,u from each measured Cp,u in large animals. The collective datasets suggest these Cb,u -preferring asymmetries are mediated by a species-independent BBB active uptake system whose identification, full characterization, and structure-activity relationships should be prioritized for potential exploitation.
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics and Metabolism, Pfizer Worldwide Research and Development, Groton Laboratories, Pfizer Inc., Groton, Connecticut, 06340.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Shaffer
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Osgood
authors.forename: Jessica Y
authors.initials: JY
authors.lastname: Mancuso
authors.forename: Angela C
authors.initials: AC
authors.lastname: Doran
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000502:physiology; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D004155:Diphenhydramine / Q000493:pharmacokinetics*; D004285:Dogs; D045604:Extracellular Fluid / Q000378:metabolism; D005260:Female; D008252:Macaca fascicularis; D008297:Male; D017551:Microdialysis / Q000379:methods; D010098:Oxycodone / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004155:Diphenhydramine; D010098:Oxycodone
keywords: CNS; blood-brain barrier; diphenhydramine; drug disposition; drug transport; preclinical pharmacokinetics