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

0090-9556/06/3406-955-960$20.00
DMD 34:955-960, 2006

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A PHARMACOKINETIC STUDY OF DIPHENHYDRAMINE TRANSPORT ACROSS THE BLOOD-BRAIN BARRIER IN ADULT SHEEP: POTENTIAL INVOLVEMENT OF A CARRIER-MEDIATED MECHANISM

Sam C. S. Au-Yeung1, Dan W. Rurak, Nancy Gruber, and K. Wayne Riggs

Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences (S.C.S.A.-Y., K.W.R.), and Child and Family Research Institute, Department of Obstetrics and Gynecology, Faculty of Medicine (D.W.R., N.G.), University of British Columbia, Vancouver, British Columbia, Canada

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 µg/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 (t1/2ß) 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 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.

Address correspondence to: Dr. K. Wayne Riggs, Faculty of Pharmaceutical Sciences, 2146 East Mall, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada. E-mail: riggskw{at}interchange.ubc.ca




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 Drug Metab. Dispos.Home page
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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