QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: dmd.106.013995v1 35/8/1285    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Au-Yeung, S. C.S. Articles by Rurak, D. W. Search for Related Content PubMed PubMed Citation Articles by Au-Yeung, S. C.S. Articles by Rurak, D. W. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB DIPHENHYDRAMINE

The Use of Microdialysis for the Study of Drug Kinetics: Central Nervous System Pharmacokinetics of Diphenhydramine in Fetal, Newborn, and Adult Sheep

Pharmacokinetics/Pharmacodynamics, Clinical Pharmacology, Quintiles, Kansas City, Missouri (S.C.S.A.-Y.); and Faculty of Pharmaceutical Sciences (K.W.R.), and Department of Obstetrics and Gynecology, Child and Family Research Institute (N.G., D.W.R.), University of British Columbia, Vancouver, British Columbia, Canada

The central nervous system (CNS) pharmacokinetics of the H₁ receptor antagonist diphenhydramine (DPHM) were studied in 100- and 120-day-old fetuses, 10- and 30-day-old newborn lambs, and adult sheep using in vivo microdialysis. DPHM was administered i.v. at five infusion rates, with each step lasting 7 h. In all ages, cerebrospinal fluid (CSF) and extracellular fluid (ECF) concentrations were very similar to each other, which suggests that DPHM between these two compartments is transferred by passive diffusion. In addition, the brain-to-plasma concentration ratios were 3 in all age groups, suggesting the existence of a transport process for DPHM into the brain. Both brain and plasma DPHM concentrations increased in a linear fashion over the dose range studied. However, the ECF/unbound plasma and CSF/unbound plasma DPHM concentration ratios were significantly higher in the fetus and lambs (5 to 6) than in the adult (3). The factors f_CSF and f_ECF, the ratios of DPHM areas under the curves (AUCs) in CSF and ECF to the plasma DPHM AUC, respectively, decreased with age, indicating that DPHM is more efficiently removed from the brain with increasing age. The extent of plasma protein binding of the drug increased with age. This study provides evidence for a transporter-mediated mechanism for the influx of DPHM into the brain and also for an efflux transporter for the drug, whose activity increases with age. Moreover, the higher brain DPHM levels in the fetus and lamb compared with the adult may explain the greater CNS effects of the drug at these ages.