P-glycoprotein influences the brain concentrations of cetirizine (Zyrtec), a second-generation non-sedating antihistamine

J Pharm Sci. 2003 Oct;92(10):2082-9. doi: 10.1002/jps.10453.


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 (PappB-->A = 56.5 nm/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 (PappB-->A + GF120918 = 296 nm/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.

Publication types

  • Comparative Study

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Animals
  • Area Under Curve
  • Brain / metabolism*
  • Cell Line
  • Cetirizine / blood
  • Cetirizine / pharmacokinetics*
  • Chromatography, Liquid
  • Dogs
  • Histamine H1 Antagonists, Non-Sedating / blood
  • Histamine H1 Antagonists, Non-Sedating / pharmacokinetics*
  • Humans
  • Hydroxyzine / blood
  • Hydroxyzine / pharmacokinetics
  • Injections, Intravenous
  • Male
  • Mass Spectrometry
  • Mice
  • Mice, Knockout
  • Permeability
  • Time Factors
  • Tissue Distribution


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Histamine H1 Antagonists, Non-Sedating
  • Hydroxyzine
  • Cetirizine