A pharmacokinetic study of diphenhydramine transport across the blood-brain barrier in adult sheep: potential involvement of a carrier-mediated mechanism

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Sam C S Au-YeungK Wayne Riggs

Abstract

The purpose of this study was to examine the disposition of diphenhydramine (DPHM) across the ovine blood-brain barrier (BBB). In six adult sheep, we characterized the central nervous system (CNS) pharmacokinetics of DPHM in brain extracellular fluid (ECF) and cerebrospinal fluid (CSF) using microdialysis in two experiments. In the first experiment, DPHM was administered via a five-step i.v. infusion (1.5, 5.5, 9.5, 13.5, and 17.5 microg/kg/min; 7 h per step). Average steady-state CNS/total plasma concentration ratios (i.e., [CNS]/[total plasma]) for steps 1 to 5 ranged from 0.4 to 0.5. However, average steady-state [CNS]/[free plasma] ratios ranged from 2 to 3, suggesting active transport of DPHM into the CNS. Plasma protein binding averaged 86.1 +/- 2.3% (mean +/- S.D.) and was not altered with increasing drug dose. Plasma, CSF, and ECF demonstrated biexponential pharmacokinetics with terminal elimination half-lives (t1/2beta) of 10.8 +/- 5.4, 3.6 +/- 1.0, and 5.3 +/- 4.2 h, respectively. The bulk flow of CSF and transport-mediated efflux of DPHM may explain the observed higher CNS clearances. In the second experiment, DPHM was coadministered with propranolol (PRN) to examine its effect on blood-brain CSF and blood-brain ECF ...Continue Reading

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Citations

Feb 13, 2013·Journal of Pharmacokinetics and Pharmacodynamics·Elizabeth C M de Lange
Apr 8, 2011·Journal of Pharmaceutical Sciences·Muhammad Waqas SadiqMargareta Hammarlund-Udenaes
Mar 19, 2014·Journal of Pharmaceutical Sciences·Christopher L ShafferAngela C Doran
Jan 21, 2012·Advanced Drug Delivery Reviews·Fabio BroccatelliLeslie Z Benet
Jun 8, 2011·Environmental Toxicology and Chemistry·Jason P BerningerBryan W Brooks
May 4, 2010·Biopharmaceutics & Drug Disposition·Toyofumi SuzukiKazuo Tomono
Jul 17, 2015·British Journal of Pharmacology·Hélène ChapySalvatore Cisternino
May 9, 2007·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Sam C S Au-YeungDan W Rurak
May 22, 2009·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Pascal AndréSalvatore Cisternino
Aug 5, 2016·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Sylvain AuvitySalvatore Cisternino
Feb 23, 2018·Expert Opinion on Drug Delivery·Zahraa S Al-Ahmady
Mar 8, 2019·Nanomaterials·Daniel Mihai TeleanuRaluca Ioana Teleanu
May 20, 2020·Frontiers in Neuroscience·Ajay KumarXiaofeng Dai
Sep 5, 2008·Environmental Science & Technology·Simon Ningsun ZhouJanusz Pawliszyn

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