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The metabolism and pharmacokinetics of 14C-cetirizine in humans.

Wood SG, John BA, Chasseaud LF, Yeh J, Chung M.

Department of Metabolism and Pharmacokinetics, Huntingdon Research Centre Ltd., Cambridgeshire, England.

This study investigated the metabolism and pharmacokinetics of cetirizine, a new H1-receptor antagonist. Single oral doses of 14C-cetirizine dihydrochloride (10 mg) in aqueous solution were administered to six healthy male volunteers. The drug was rapidly absorbed: The peak mean concentration of radioactivity (359 ng-equivalents/mL) and of unchanged drug (341 ng/mL) were achieved within one hour. Mean concentrations of cetirizine declined biexponentially and had a mean elimination half-life of 7.4 hours. The drug was excreted quite rapidly, with 60% of the dose recovered in the 24-hour urine. An additional 10% was excreted in urine over the next four days. Approximately 10% of the dose was excreted in feces over the five-day study period. The dose was excreted mainly as the unchanged drug. Examination of the radioactive compounds present in the plasma, and excreted in the urine and feces indicate that there is little metabolism of cetirizine. One minor metabolite, formed by oxidative O-dealkylation of the cetirizine side chain, was detected in plasma and feces.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2892447&dopt=Abstract cetirizine Zyrtec



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Receptor effects of cetirizine.

Snyder SH, Snowman AM.

Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland.

First-generation H1-antagonist antihistamines such as hydroxyzine have a significant ability to cross the blood-brain barrier and cause sedation, which limits their usefulness in the treatment of allergic disorders. Cetirizine, a carboxylated metabolite of hydroxyzine, possesses the parent compound's antihistaminic activity but does not cause sedation. This lack of CNS effects may be due to cetirizine's greater selectivity or potency at H1 receptors in the brain, compared with its effects at the receptors involved in sedation, or it may result from the agent's relative exclusion from the CNS compartment. We compared cetirizine's activity at central H1 sites with the activity of hydroxyzine and terfenadine. We also compared the abilities of cetirizine and three other antihistamines to cross the blood-brain barrier. We found the drugs' potency at H1 receptors in the CNS to be similar to their activities in other tissues. However, their selectivity varied widely. Cetirizine, in fact, failed to bind at any of the receptors investigated except H1 sites, even at concentrations as high as 10 micron. Both hydroxyzine and D-chlorpheniramine crossed the blood-brain barrier in significant amounts. Terfenadine did so to a much lesser extent, and cetirizine passed into the CNS only half as readily as terfenadine. We suggest that cetirizine's reduced incidence of sedative side effects may stem partly from its selectivity for H1 receptors over sites involved in sedation, and partly from its relative exclusion from the CNS.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2892448&dopt=Abstract cetirizine Zyrtec



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Single dose pharmacokinetics of cetirizine in young and elderly volunteers.

Lefebvre RA, Rosseel MT, Bernheim J.

Heymans Institute of Pharmacology, University of Gent Medical School, Belgium.

The pharmacokinetics of the H1-receptor antagonist cetirizine were studied from 0 to 48 h after a single oral intake of 10 mg in 10 elderly volunteers (60 to 90 years) and in 10 young healthy volunteers (21 to 29 years). In young healthy volunteers about 60% of an oral dose of cetirizine was excreted in the urine in unchanged form. Mean plasma concentrations were slightly higher in the elderly subjects. Cmax (362 ng/ml), Tmax (1.30 h), terminal half-life (11.8 h) and AUC infinity (4316 ng.h/ml) in the elderly subjects were somewhat higher than in the young subjects (Cmax: 337 ng/ml, Tmax: 1.12 h, terminal half-life: 10.6 h, AUC: 3721 ng.h/ml), but the difference was not significant. The mean cumulative urinary excretion at 32 h was significantly lower in the elderly subjects. It is concluded that the slight differences in pharmacokinetics of cetirizine between young and elderly subjects after single oral intake can be attributed to the decreased renal clearance in the elderly.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2908109&dopt=Abstract cetirizine Zyrtec



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Inhibition of histamine and allergen skin wheal by cetirizine in four animal species.

De Vos C, Maleux MR, Baltes E, Gobert J.

Research Centre, UCB Pharmaceutical Sector, Chemin du Foriest, Belgium.

Histamine-induced skin reactions were studied in four animal species. Cetirizine displayed very potent oral antihistaminic activity in this model. In rats, the dose that reduced the reaction by 50% in comparison to controls was 4.2 mumol/kg and between 0.1 and 0.4 mumol/kg for the other species (mice, guinea pigs, and dogs). Cetirizine also inhibited the immediate hypersensitivity reaction induced by Ascaris extract in dogs. By the oral route, cetirizine had a more potent and longer acting activity than mepyramine, clemastine, terfenadine, astemizole, and hydroxyzine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2959177&dopt=Abstract cetirizine Zyrtec



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Inhibition of eosinophil chemotaxis by a new antiallergic compound (cetirizine).

Leprevost C, Capron M, De Vos C, Tomassini M, Capron A.

Centre d'Immunologie et de Biologie Parasitaire, Unite mixte INSERM U167-CNRS 624, Institut Pasteur, Lille, France.

The in vivo inhibitory effect of a new antiallergic, anti-H1 drug, cetirizine, on eosinophil attraction at skin sites challenged with various stimuli has been recently suggested. In the present work, we confirmed that this molecule, at therapeutical concentration, has a potent inhibitory action on eosinophil response to different chemoattractant mediators such as platelet-activating factor (PAF acether) and N-formyl methionyl leucyl phenyl alanyl in vitro. Another anti-H1 drug, polaramine, did not show this effect at the same concentration. These findings suggest that cetirizine in addition to its antihistaminic effect could also play a direct inhibitory effect on eosinophil recruitment. Moreover, cetirizine was not toxic for eosinophils and did not induce degranulation, as shown by the absence of peroxidase release. Comparison between cetirizine and a PAF acether antagonist (BN 52021) suggested that cetirizine did not act by a PAF receptor-blocking activity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2971624&dopt=Abstract cetirizine Zyrtec



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Pharmacologic heterogeneity of human lung and colon cells: effect of terfenadine and cetirizine.

Fabre JM, Marty-Ane C, Alauzen M, Souques F, Bousquet J, Campbell AM.

Clinique des Maladies Respiratoires and CJF-INSERM 92-10, Centre Hospitalier Universitaire, Montpellier, France.

H1-blockers may have antiallergic properties which cause the blocking of eicosanoid release, and the effect of these drugs may differ according to the phenotype of mast cells. This study examined the ability of terfenadine and cetirizine to inhibit the release of arachidonic acid-derived mediators from human lung and colon cells. Dispersed cells were challenged with anti-IgE in the presence or absence of 10 microM of terfenadine or cetirizine, and the release of prostaglandin (PG)D2 and leukotriene (LT)C4/D4 was assessed by enzyme immunoassay (EIA). Terfenadine caused significant inhibition of both PGD2 and LTC4/D4 (49 +/- 9 and 29 +/- 19%, respectively) from human lung cells but had a less marked effect on PGD2 release from human colon cells (21 +/- 9% for PGD2 and 18 +/- 9% for LTC4/D4). In contrast, although cetirizine caused significant inhibition of both mediators measured in lung cells (38 +/- 16% for PGD2 and 34 +/- 19% for LTC4), it did not cause any significant inhibition of either mediator from human colon cells. These findings suggest that H1-antagonists may have additional properties, and the differential effects of cetirizine on lung and colon tissue may indicate differences in mast cell phenotype.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7573821&dopt=Abstract cetirizine Zyrtec