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

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Polli JW, Baughman TM, Humphreys JE, Jordan KH, Mote AL, Salisbury JA, Tippin TK, Serabjit-Singh CJ

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.

PubMed ID

14502547 [ View in PubMed

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Abstract

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.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Cetirizine	P-glycoprotein 1	Protein	Humans	No	Substrate Inhibitor	Details