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Drug Metabolism and Disposition Fast Forward
First published on March 1, 2006; DOI: 10.1124/dmd.105.007898

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K Wayne Riggs
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Received for publication October 18, 2005.
Revised February 23, 2006.
Accepted for publication February 24, 2006.

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

Sam CS Au Yeung 1, Dan W Rurak 2, Nancy Gruber 2, K Wayne Riggs 2*

1 Quintiles, Inc. 2 University of British Columbia

* Address correspondence to: E-mail: riggskw{at}interchange.ubc.ca

Abstract

The purpose of this study was to examine the disposition of diphenydramine (DPHM) across the ovine blood-brain barrier (BBB). In 6 adult sheep we characterized the CNS pharmacokinetics of DPHM in brain extracellular fluid (ECF) and cerebrospinal fluid (CSF) using microdialysis in 2 experiments. In the first experiment, DPHM was administered via a 5-step i.v infusion (1.5, 5.5, 9.5, 13.5, and 17.5 µg/kg/min; 7 h per step). Average steady-state CNS/total plasma concentration ratios (i.e. [CNS]/[total plasma]) for steps 1-5 ranged from 0.4-0.5. However, average steady-state [CNS]/[free plasma] ratios ranged from 2-3, suggesting active transport of DPHM into the CNS. Plasma protein binding averaged 86.1±2.3% (mean±SD) and was not altered with increasing drug dose. Plasma, CSF, and ECF demonstrated biexponential pharmacokinetics with terminal elimination half lives (t1/2{beta}) 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 co-administered with propranolol (PRN) to examine its effect on blood-brain CSF and blood-brain ECF DPHM relationships. Plasma total DPHM concentration decreased by 12.8±6.3% during PRN, whereas ECF and CSF concentrations increased (88.1±45.4 and 91.6±34.3%, respectively). This increase may be due to the inhibitory effect of PRN on a transporter-mediated efflux mechanism for DPHM brain elimination.


Key words: active transport, blood-brain barrier, blood-CNS transport, CNS pharmacokinetics, distribution, excretion, pharmacokinetics


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S. C.S. Au-Yeung, K. W. Riggs, N. Gruber, and D. W. Rurak
The Use of Microdialysis for the Study of Drug Kinetics: Central Nervous System Pharmacokinetics of Diphenhydramine in Fetal, Newborn, and Adult Sheep
Drug Metab. Dispos., August 1, 2007; 35(8): 1285 - 1291.
[Abstract] [Full Text] [PDF]


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