P‐glycoprotein Influences the Brain Concentrations of Cetirizine (Zyrtec®), a Second‐Generation Non‐Sedating Antihistamine

Recent in vitro studies have suggested that P‐glycoprotein (Pgp) and passive membrane permeability may influence the brain concentrations of non‐sedating (second‐generation) antihistamines. The purpose of this study was to determine the importance of Pgp‐mediated efflux on the in vivo brain distribu...

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Bibliographic Details
Published in:Journal of pharmaceutical sciences 2003-10, Vol.92 (10), p.2082-2089
Main Authors: Polli, Joseph W., Baughman, Todd M., Humphreys, Joan E., Jordan, Kelly H., Mote, Angela L., Salisbury, Jo A., Tippin, Timothy K., Serabjit‐Singh, Cosette J.
Format: Article
Language:English
Subjects:
Animals
antihistamines
Area Under Curve
ATP-Binding Cassette, Sub-Family B, Member 1 - genetics
ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism
Biological and medical sciences
blood-brain barrier
Brain - metabolism
Cell Line
Cetirizine - blood
Cetirizine - pharmacokinetics
Chromatography, Liquid
Dogs
drug interaction
efflux transporter
Histamine and antagonists. Allergy
Histamine H1 Antagonists, Non-Sedating - blood
Histamine H1 Antagonists, Non-Sedating - pharmacokinetics
Humans
Hydroxyzine - blood
Hydroxyzine - pharmacokinetics
in vivo
in vivo, blood–brain barrier
Injections, Intravenous
knockout mice
Male
Mass Spectrometry
Medical sciences
Mice
Mice, Knockout
P-glycoprotein
Permeability
Pharmacology. Drug treatments
sedation
Time Factors
Tissue Distribution
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Summary:Recent in vitro studies have suggested that P‐glycoprotein (Pgp) and passive membrane permeability may influence the brain concentrations of non‐sedating (second‐generation) antihistamines. The purpose of this study was to determine the importance of Pgp‐mediated efflux on the in vivo brain distribution of the non‐sedating antihistamine cetirizine (Zyrtec®), and the structurally related sedating (first‐generation) antihistamine hydroxyzine (Atarax®). In vitro MDR1‐MDCKII monolayer efflux assays demonstrated that cetirizine was a Pgp substrate (B → A/A → B + GF120918 ratio = 5.47) with low/moderate passive permeability (Papp B → A = 56.5nm/s). In vivo, the cetirizine brain‐to‐free plasma concentration ratios (0.367 to 4.30) were 2.3‐ to 8.7‐fold higher in Pgp‐deficient mice compared with wild‐type mice. In contrast, hydroxyzine was not a Pgp substrate in vitro (B → A/A → B ratio = 0.86), had high passive permeability (Papp B → A + GF120918 = 296nm/s), and had brain‐to‐free plasma concentration ratios >73 in both Pgp‐deficient and wild‐type mice. These studies demonstrate that Pgp‐mediated efflux and passive permeability contribute to the low cetirizine brain concentrations in mice and that these properties account for the differences in the sedation side‐effect profiles of cetirizine and hydroxyzine. © 2003 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:2082–2089, 2003
ISSN:0022-3549
1520-6017
DOI:10.1002/jps.10453