Diphenhydramine has Similar Interspecies Net Active Influx at the Blood–Brain Barrier. Issue 5 (13th March 2014)

• Record Type: Journal Article
• Authors: Shaffer, Christopher L.; Osgood, Sarah M.; Mancuso, Jessica Y.; Doran, Angela C.
• Is Part Of: Journal of pharmaceutical sciences. Volume 103:Issue 5(2014:May)
• Page Start: 1557
• Page End: 1562
• Publication Date: 2014-03-13
• Subjects: Pharmacy -- Periodicals; 615.1
• DOI: 10.1002/jps.23927
• Languages: English
• ISSNs: 0022-3549

Abstract

<abstract abstract-type="main" xml:lang="en"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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 (<italic>C</italic><sub>ISF</sub>) than unbound plasma compound concentrations (<italic>C</italic><sub>p, u</sub>). Oxycodone and diphenhydramine have <italic>C</italic><sub>ISF</sub>:<italic>C</italic><sub>p, u</sub> of 3.0 and 5.5, respectively, while CE‐157119 has an unbound brain compound concentration (<italic>C</italic><sub>b, u</sub>):<italic>C</italic><sub>p, u</sub> of 3.90; <italic>C</italic><sub>b, u</sub> is a high‐confidence <italic>C</italic><sub>ISF</sub> surrogate. However, only CE‐157119 has published dog and nonhuman primate (nhp) neuropharmacokinetics, which show similar <italic>C</italic><sub>b, u</sub>:<italic>C</italic><sub>p, u</sub> (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 <italic>C</italic><sub>b, u</sub>:<italic>C</italic><sub>p, u</sub> (3.90) was consistent with prior steady‐state‐derived <italic>C</italic><sub>ISF</sub>:<italic>C</italic><sub>p, u</sub> 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 <italic>C</italic><sub>b, u</sub>‐favoring disequilibria in these mammals. Accordingly, the applied <italic>C</italic><sub>b, u</sub>‐forecasting methodology accurately predicted [estimated mean (95% confidence interval) of 0.84 (0.68, 1.05)] <italic>C</italic><sub>b, u</sub> from each measured <italic>C</italic><sub>p, u</sub> in large animals. The collective datasets suggest these <italic>C</italic><sub>b, u</sub>‐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 J Pharm Sci 103:1557–1562, 2014</p> </abstract>