Hydroxyzine and cetirizine pharmacokinetics and pharmacodynamics after oral and intravenous administration of hydroxyzine to healthy dogs

Abstract

Pharmacokinetic parameters of hydroxyzine and its active metabolite cetirizine were determined after oral and intravenous administration of 2 mg kg(-1) of hydroxyzine to six healthy dogs. Plasma drug levels were determined with high-pressure liquid chromatography. Pharmacodynamic studies evaluated the suppressive effect on histamine and anticanine IgE-mediated cutaneous wheal formation. Pharmacokinetic and pharmacodynamic correlations were determined with computer modelling. The mean systemic availability of oral hydroxyzine was 72%. Hydroxyzine was rapidly converted to cetirizine regardless of the route of administration. The mean area-under-the-curve was eight and ten times higher for cetirizine than hydroxyzine after intravenous and oral dosing, respectively. After oral administration of hydroxyzine, the mean peak concentration of cetirizine was approximately 2.2 microg mL(-1) and that of hydroxyzine 0.16 microg mL(-1). The terminal half-life for cetirizine varied between 10 and 11 h after intravenous and oral administration of hydroxyzine. A sigmoidal relationship was fit to the data comparing cetirizine plasma concentration to wheal suppression. Maximum inhibition (82% and 69% for histamine and anticanine IgE-mediated skin reactions, respectively) was observed during the first 8 h, which correlated with a plasma concentration of cetirizine greater than 1.5 microg mL(-1). Pharmacological modelling suggested that increasing either hydroxyzine dosages or frequencies of administration would not result in histamine inhibition superior to that obtained with twice daily hydroxyzine at 2 mg kg(-1). In conclusion, there was rapid conversion of hydroxyzine to cetirizine. The reduction of wheal formation appeared almost entirely due to cetirizine. Pharmacodynamic modelling predicted that maximal antihistamine effect would occur with twice daily oral administration of hydroxyzine at 2 mg kg(-1).

Cetirizine per os: exposure and antihistamine effect in the dog

“…3). The antihistamine response in this study is consistent with the reported antihistamine response to cetirizine after administration of 2 mg/kg hydroxyzine per os daily in dogs, while medication with 1 mg/kg cetirizine orally once daily results in a lower antihistamine response [10, 12]. These conflicting results may be explained by insufficient plasma exposure when lower doses of cetirizine than in this study are used.…”

“…These conflicting results may be explained by insufficient plasma exposure when lower doses of cetirizine than in this study are used. Due to the fairly long half-life (median 10 h) of cetirizine, 2 mg/kg daily dose is sufficient to maintain plasma concentration exceeding the median IC 50 value (0.33 µg/mL) for 24 h. This quantitative information is similar to the median half-life of cetirizine (9.7 h) and the IC 50 -value (0.6 µg/mL), after administration of hydroxyzine, reported by Bizikova et al [12]. …”

“…A dose of 0.5 mg/kg cetirizine is unlikely to give plasma concentrations above the potency ( IC 50 ) value. Hydroxyzine at 2 mg/kg prevents wheal and flare reactions due to intradermal skin injections, mainly due to the effects of the active metabolite cetirizine [12]. The reduction in skin lesion score shown in the study by Eichenseer et al [17] may be due to the higher total dose of antihistamines given by means of combining two different antihistamines.…”

“…Compared with clemastine, the antihistamine response to the second generation antihistamine cetirizine (1 mg/kg once daily) in the dog is more efficacious, around 30–80% with a marked variations between animals and between studies [10, 11]. This can be compared with the antihistamine response after oral administration of 2 mg/kg hydroxyzine, which is around 90% and shows lower inter-individual variability [12]. Hydroxyzine is metabolized to cetirizine, which is considered the active substance to the antihistamine response after hydroxyzine administration.…”

Enantioselective determination of cetirizine in human plasma by normal-phase liquid chromatography–atmospheric pressure chemical ionization–tandem mass spectrometry

“…A number of analytical methods have been used to quantify cetirizine in pharmaceutical formulations and biological fluids (serum, plasma, urine, and tears) including high performance thin layer chromatography (HPTLC) [6], gas chromatography [7], HPLC with ultraviolet detection [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24], HPLC with fluorescence detection (pre-column derivatization) [25], HPLC with on-line liquid scintillation counting [26], and capillary electrophoresis (CE) [14,[27][28][29]. However, these methods have a number of disadvantages; for example, they require a large volume of sample (≥1.0 mL), and have long run time, low separation resolution, and poor sensitivity.…”