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 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.
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019540:Area Under Curve; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D017332:Cetirizine / Q000097:blood / Q000493:pharmacokinetics*; D002853:Chromatography, Liquid; D004285:Dogs; D039563:Histamine H1 Antagonists, Non-Sedating / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D006919:Hydroxyzine / Q000097:blood / Q000493:pharmacokinetics; D007275:Injections, Intravenous; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D018345:Mice, Knockout; D010539:Permeability; D013997:Time Factors; D014018:Tissue Distribution
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D039563:Histamine H1 Antagonists, Non-Sedating; D006919:Hydroxyzine; D017332:Cetirizine