RT Journal Article
SR Electronic
T1 A PHARMACOKINETIC STUDY OF DIPHENHYDRAMINE TRANSPORT ACROSS THE BLOOD-BRAIN BARRIER IN ADULT SHEEP: POTENTIAL INVOLVEMENT OF A CARRIER-MEDIATED MECHANISM
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 955
OP 960
DO 10.1124/dmd.105.007898
VO 34
IS 6
A1 Sam C. S. Au-Yeung
A1 Dan W. Rurak
A1 Nancy Gruber
A1 K. Wayne Riggs
YR 2006
UL http://dmd.aspetjournals.org/content/34/6/955.abstract
AB 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 (t1/2β) 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. The American Society for Pharmacology and Experimental Therapeutics