title: Histamine H1 receptor antagonism by cetirizine in isolated guinea pig tissues: influence of receptor reserve and dissociation kinetics.
abstract: We characterised histamine H(1) receptor antagonism by cetirizine and its enantiomers on isolated guinea pig ileum and trachea. Competitive or mixed (competitive and apparent noncompetitive) antagonism profiles were observed. The order of potency was: chlorpheniramine> or =mepyramine>levocetirizine>cetirizine> or =terfenadine>loratadine>dextrocetirizine. The inhibitory effects of cetirizine, levocetirizine, terfenadine and loratadine were slowly reversible compared to those of dextrocetirizine or mepyramine. Cetirizine and its enantiomers were inactive on L-type Ca(2+) channels. Reduction of the histamine H(1) receptor reserve by dibenamine in the ileum (100-fold higher than in the trachea) showed a gradual change from the competitive profile of dextrocetirizine and mepyramine to a mixed profile. The present results show that cetirizine and levocetirizine are selective competitive but slowly reversible histamine H(1) receptor antagonists. Their mixed antagonism profile observed in the trachea can be explained by the small receptor reserve present in this tissue compared to the ileum and their very slow dissociation rate from the histamine H(1) receptor.
authors.affiliation: UCB Pharma, Allergo-Respiratory Pharmacology Department, Chemin du Foriest, Bâtiment R1, B-1420 Braine l'Alleud, Belgium. Bernard.Christophe@UCB-Group.com
authors.forename: Bernard
authors.initials: B
authors.lastname: Christophe
authors.forename: Brigitte
authors.initials: B
authors.lastname: Carlier
authors.forename: Michel
authors.initials: M
authors.lastname: Gillard
authors.forename: Pierre
authors.initials: P
authors.lastname: Chatelain
authors.forename: Mike
authors.initials: M
authors.lastname: Peck
authors.forename: Roy
authors.initials: R
authors.lastname: Massingham
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D017332:Cetirizine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006632:Histamine / Q000378:metabolism / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000378:metabolism / Q000494:pharmacology*; D007082:Ileum / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D011969:Receptors, Histamine H1 / Q000378:metabolism*; D014132:Trachea / Q000187:drug effects* / Q000378:metabolism
chemical_list: D006634:Histamine H1 Antagonists; D011969:Receptors, Histamine H1; D006632:Histamine; D017332:Cetirizine