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

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. -->

ISSN:	0022-3549
DOI:	10.1002/jps.10453
Přístupová URL adresa:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d5448bc4ec1f72563033849add475017 https://doi.org/10.1002/jps.10453
Rights:	CLOSED
Přírůstkové číslo:	edsair.doi.dedup.....d5448bc4ec1f72563033849add475017
Autor:	Jo A. Salisbury, Joan E. Humphreys, Cosette J. Serabjit-Singh, Todd M. Baughman, Timothy K. Tippin, Kelly H. Jordan, Joseph W. Polli, Angela L. Mote
Rok vydání:	2003
Předmět:	Male Histamine H1 Antagonists Non-Sedating Time Factors Membrane permeability medicine.medical_treatment Pharmaceutical Science Pharmacology Mass Spectrometry Permeability Cell Line Mice Dogs Pharmacokinetics In vivo polycyclic compounds medicine Animals Humans Tissue Distribution ATP Binding Cassette Transporter Subfamily B Member 1 P-glycoprotein Mice Knockout Hydroxyzine biology Chemistry Antagonist Brain Cetirizine Area Under Curve Injections Intravenous biology.protein Antihistamine Chromatography Liquid medicine.drug
Zdroj:	Journal of Pharmaceutical Sciences. 92:2082-2089
ISSN:	0022-3549
DOI:	10.1002/jps.10453
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d5448bc4ec1f72563033849add475017 https://doi.org/10.1002/jps.10453 Zobrazit plný text záznamu Plný text