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Molecular properties and pharmacokinetic behavior of cetirizine, a zwitterionic H1-receptor antagonist.

Pagliara A, Testa B, Carrupt PA, Jolliet P, Morin C, Morin D, Urien S, Tillement JP, Rihoux JP.

Institut de Chimie Therapeutique, Universite de Lausanne, Switzerland.

The ionization and lipophilicity behavior of the antihistamine (H1-receptor antagonist) cetirizine was investigated, showing the drug to exist almost exclusively as a zwitterion in the pH region 3.5-7.5. In this pH range, its octanol/water lipophilicity is constant and low compared to cationic antihistamines (log D = log PZ = 1.5), whereas its H-bonding capacity is relatively large (delta log PZ > or = 3.1). Conformational, electronic, and lipophilicity potential calculations revealed that zwitterionic cetirizine experiences partial intramolecular charge neutralization in folded conformers of lower polarity. Pharmacokinetic investigations have shown the drug to be highly bound to blood proteins, mainly serum albumin, and to have a low brain uptake, explaining its lack of sedative effects. As such, cetirizine does not differ from "second-generation" antihistamines. In contrast, its very low apparent volume of distribution in humans (0.4 L kg-1, smaller than that of exchangeable water) implies a low affinity for lean tissues such as the myocardium and is compatible with the absence of cardiotoxicity of the drug. The zwitterionic nature and modest lipophilicity of cetirizine may account for this pharmacokinetic behavior. The suggestion is offered that cetirizine and analogous zwitterions, whose physicochemical, pharmacokinetic, and pharmacodynamic properties differ from those of "first-" and "second-generation" drugs in this class, could be considered as "third-generation" antihistamines.

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Cetirizine and hydrocortisone differentially regulate ICAM-1 expression and chemokine release in cultured human keratinocytes.

Albanesi C, Pastore S, Fanales-Belasio E, Girolomoni G.

Laboratory of Immunology, Istituto Dermopatico dell'Immacolata, IRCCS, Rome, Italy.

BACKGROUND: Cetirizine is a H1 histamine antagonist which possesses anti-inflammatory properties through inhibition of leucocyte recruitment and activation, and reduction of ICAM-1 expression on mucosal epithelial cells. No studies have addressed the potential anti-inflammatory activities of cetirizine on skin keratinocytes. OBJECTIVES: Cetirizine and hydrocortisone were compared in their capacity to counteract human keratinocytes activation by IFNgamma. In particular, expression of immuno-modulatory membrane molecules and chemokine release have been examined. METHODS: Keratinocyte cultures established from normal skin of healthy donors were activated by IFNgamma (100-500 U/mL) in the absence or presence of cetirizine (10(-3)-10(3) microM) or hydrocortisone (10(-3)-10(2) microM), and tested for expression of ICAM-1, HLA-DR, MHC class I and CD40 as well as for release of RANTES, IL-8, macrophage chemotactic protein-1 (MCP-1) and granulocyte macrophage-colony stimulating factor (GM-CSF). RESULTS: Cetirizine at high concentrations (10(2)-10(3) microM) markedly inhibited IFNgamma-induced expression of membrane ICAM-1, HLA-DR and up-regulation of MHC class I, but had no effect on CD40 expression. In contrast, hydrocortisone (10(2) microM) enhanced IFNgamma-induced membrane ICAM-1, reduced expression of HLA-DR and did not alter expression of MHC class I and CD40. Consistently, high doses of cetirizine decreased, whereas hydrocortisone increased, soluble ICAM-1 levels in the supernatants of IFNgamma-treated keratinocytes. The inhibiting and stimulating effects of cetirizine and hydrocortisone, respectively, on ICAM-1 expression were confirmed at the mRNA level by Northern blot analysis. Finally, cetirizine, but not hydrocortisone, inhibited the release of MCP-1 and RANTES from IFNgamma-stimulated keratinocytes. In contrast, hydrocortisone, but not cetirizine, reduced GM-CSF and IL-8 release. CONCLUSIONS: The results indicate that cetirizine has the capacity to block the IFNgamma-induced activation of keratinocytes, and thus can exert important regulatory effects on TH1 cell-mediated immune responses in the skin. The high doses required for evidencing these activities suggest the potential benefits of a topical use of cetirizine.

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Effects of cetirizine dihydrochloride on human lymphocytes in vitro: evaluation of chromosome aberrations and sister chromatid exchanges.

Vlastos D, Stephanou G, Demopoulos NA.

Department of Biology, University of Patras, Greece.

The ability of cetirizine dihydrochloride, an antihistaminic agent, to induce chromosome aberrations as well as sister chromatid exchanges (SCEs) was evaluated in human lymphocyte cultures treated in vitro. The following concentrations were tested: 25, 50, 75, 100 and 200 micrograms/ml. The results of our study revealed that cetirizine dihydrochloride is capable of inducing chromosome aberrations, at least at the higher concentrations studied, 100 and 200 micrograms/ml. The majority of aberrations was of chromatid type. Cetirizine is also a weak inducer of SCEs. Further studies are now warranted in order to define the in vivo cytogenetic activity of cetirizine in humans.

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Spectrophotometric and high performance liquid chromatographic determination of cetirizine dihydrochloride in pharmaceutical tablets.

el Walily AF, Korany MA, el Gindy A, Bedair MF.

Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Alexandria University, Egypt.

Derivative spectrophotometric, colorimetric and high performance liquid chromatographic methods, for the determination of the antihistaminic cetirizine dihydrochloride in tablet form were described. Spectrophotometrically, cetirizine was determined by the measurement of its first (1D) and second (2D) derivative amplitudes at 239 (peak) and 243-233 nm (peak-to-trough), respectively. The aqueous solutions obeyed Beer's law in the concentration ranges of 1.2-10.0 and 0.8-10.0 micrograms ml-1 for 1D and 2D measurements, respectively. The colorimetric procedure was based on measuring the absorbency of the coloured chromogen resulted from the reaction between cetirizine sodium salt in polar solvent (DMF) and chloranil at 556 nm. The relation with concentrations was linear over 120-250 micrograms ml-1. Optimization of the reaction conditions was studied. At the same time, investigation of the complex formed was made with respect to its composition and the associated constant. A simple liquid chromatographic assay has been developed for the determination of cetirizine dihydrochloride in the presence of one of its synthesis precursor (hydroxyzine hydrochloride). A Bondapak-C18 column was used with a mobile phase consisting of acetonitrile/0.01 M ammonium dihydrogen phosphate (32:68, v/v) containing 0.1% w/v tetrabutyl ammonium hydrogen sulphate adjusted to pH 3 with phosphoric acid at a flow rate of 2 ml min-1. With salicylic acid as internal standard, quantitation was achieved with UV detection at 230 nm based on the peak height ratios. Beer's law was obeyed in a concentration range of 3-35 micrograms ml-1 and the regression line equation was derived with a correlation coefficient of 0.9999. The validity of the methods was further confirmed using the standard addition method. The proposed procedures were successfully applied to the determination of cetirizine in bulk and tablet form, with high percentage of recovery, good accuracy and precision.

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Molecular basis for the lack of HERG K+ channel block-related cardiotoxicity by the H1 receptor blocker cetirizine compared with other second-generation antihistamines.

Taglialatela M, Pannaccione A, Castaldo P, Giorgio G, Zhou Z, January CT, Genovese A, Marone G, Annunziato L.

Section of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples Federico II, 80131 Naples, Italy. mtaglial unina.it

In the current study, the potential blocking ability of K+ channels encoded by the human ether-a-go-go related gene (HERG) by the piperazine H1 receptor antagonist cetirizine has been examined and compared with that of other second-generation antihistamines (astemizole, terfenadine, and loratadine). Cetirizine was completely devoid of any inhibitory action on HERG K+ channels heterologously expressed in Xenopus laevis oocytes in concentrations up to 30 microM. On the other hand, terfenadine and astemizole effectively blocked HERG K+ channels with nanomolar affinities (the estimated IC50 values were 330 and 480 nM, respectively), whereas loratadine was approximately 300-fold less potent (IC50 approximately 100 microM). In addition, in contrast to terfenadine, cetirizine did not show use-dependent blockade. In SH-SY5Y cells, a human neuroblastoma clone that constitutively expresses K+ currents carried by HERG channels (IHERG), as well as in human embryonic kidney 293 cells stably transfected with HERG cDNA, extracellular perfusion with 3 microM cetirizine did not exert any inhibitory action on IHERG. Astemizole (3 microM), on the other hand, was highly effective. Terfenadine (3 microM) caused a marked (approximately 80%) inhibition of IHERG in SH-SY5Y cells, whereas loratadine, at the same concentration, caused a 40% blockade. Furthermore, the application of cetirizine (3 microM) on the intracellular side of the membrane of HERG-transfected human embryonic kidney 293 cells did not affect IHERG, whereas the same intracellular concentration of astemizole caused a complete block. The results of the current study suggest that second-generation antihistamines display marked differences in their ability to block HERG K+ channels. Cetirizine in particular, which possesses more polar and smaller substituent groups attached to the tertiary amine compared with other antihistamines, lacks HERG-blocking properties, possibly explaining the absence of torsade de pointes ventricular arrhythmias associated with its therapeutical use.

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Effects of cetirizine on the delayed K+ currents in cardiac cells: comparison with terfenadine.

Carmeliet E.

C.E.H.A., University Leuven, Gasthuisberg, Belgium.

1. The aim of the present experiments was to analyse the effect of the H1-histamine antagonist, cetirizine, on the delayed K+ currents in cardiac cells and to compare its effects with another H1-histamine antagonist terfenadine, known to possess proarrhythmic effects. 2. Whole cell currents were measured by use of the single electrode patch-clamp technique in rabbit and guinea-pig myocytes. 3. The activation relationship for the IKr current in rabbit ventricular myocytes was depressed and its voltage-dependence shifted in the negative direction with a V1/2 value -13.4+/-2.4 mV under control conditions which changed to -19.1+/-1.9 mV (n=4) in the presence of 0.1 mM cetirizine. 4 In rabbit ventricular myocytes the IC50 for block of IKr was 108+/-8 microM (n=5); in guinea-pig ventricular myocytes this concentration of cetirizine reduced the rapidly activating component IKr to 49+/-4.5% (n=5), while the slowly activating IKs was less affected and only inhibited to 79+/-2.3% (n=5). 5 The block of IKr did not show use-dependence and the time course of the tail current was not changed, suggesting rested-state block or fast activated-state block and no rapid recovery on deactivation. No important difference was found in the activity of the two enantiomers of cetirizine. 6 Terfenadine in comparison was more potent in blocking IKr, the IC50 being 96+/-15 nM (n=6). 7 Based on the present results and information in the literature on binding, it was concluded that cetirizine is a relatively selective H1-histamine receptor antagonist, with minor effects on K+ currents. The IC50 concentration for IKr block in heart cells was 1.000 times higher than the concentrations needed to block H1 histamine receptors. The occurrence of cardiac arrhythmias due to K+ current blockade is therefore unlikely with this drug.

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