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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