Diphenhydramine has Similar Interspecies Net Active Influx at the Blood-Brain Barrier

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. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.