Pharmacokinetics of hydroxyzine and cetirizine following oral administration of hydroxyzine to exercised Thoroughbred horses.

Hydroxyzine is a first-generation antihistamine and cetirizine, a second-generation antihistamine and active metabolite of hydroxyzine. Hydroxyzine is commonly used in performance horses and as such its use in closely regulated; however, there are no published studies suitable for establishing appropriate regulatory recommendations. In the current study, 12 exercised Thoroughbred research horses received a single oral administration of 500 mg of hydroxyzine. Blood and urine samples were collected prior to and up to 96 hr postdrug administration and concentrations of hydroxyzine and cetirizine determined using liquid chromatography-tandem mass spectrometry. A joint parent/metabolite population 2-compartment pharmacokinetic model with first-order absorption and elimination was utilized to describe the pharmacokinetics of both compounds. Serum hydroxyzine and cetirizine concentrations were above the limit of quantitation (0.1 ng/ml) of the assay at 96 hr (the last time point sampled). The terminal half-life was 7.41 and 7.13 hr for hydroxyzine and cetirizine, respectively. Findings from this study suggest that a prolonged withdrawal time should be observed if this compound is used in performance administered to performance horses and is classified as prohibited substance by the applicable regulatory body.

D-Optimal mixture design optimization of an HPLC method for simultaneous determination of commonly used antihistaminic parent molecules and their active metabolites in human serum and urine.

This study describes a specific, precise, sensitive and accurate method for simultaneous determination of hydroxyzine, loratadine, terfenadine, rupatadine and their main active metabolites cetirizine, desloratadine and fexofenadine, in serum and urine using meclizine as an internal standard. Solid-phase extraction method for sample clean-up and preconcentration of analytes was carried out using Phenomenex Strata-X-C and Strata X polymeric cartridges. Chromatographic analysis was performed on a Phenomenex cyano (150 × 4.6 mm i.d., 5 µm) analytical column. A D-optimal mixture design methodology was used to evaluate the effect of changes in mobile phase compositions on dependent variables and optimization of the response of interest. The mixture design experiments were performed and results were analyzed. The region of ideal mobile phase composition consisting of acetonitrile-methanol-ammonium acetate buffer (40 mm; pH 3.8 adjusted with acetic acid): 18:36:46% v/v/v was identified by a graphical optimization technique using an overlay plot. While using this optimized condition all analytes were baseline resolved in <10 min. Solvent mixtures were delivered at 1.5 mL/min flow rate and analytes peaks were detected at 222 nm. The proposed bioanalytical method was validated according to US Food and Drug Administration guidelines. The proposed method was sensitive with detection limits of 0.06-0.15 µg/mL in serum and urine samples. Relative standard deviation for inter- and intra-day precision data was found to be <7%. The proposed method may find application in the determination of selected antihistaminic drugs in biological fluids.

Enantioselective UFLC Determination of Hydroxyzine Enantiomers and Application to a Pharmacokinetic Study in Rabbits.

Hydroxyzine is the first generation H1 receptor antagonist drug that is now marketed as a racemic mixture. The paper describes a validated enantioselective liquid chromatography method for the resolution of hydroxyzine enantiomers and cyclizine (internal standard) from 200 µL of rabbit plasma by liquid-liquid extraction technique using n-hexane and isopropanol. Hydroxyzine enantiomers were resolved at 10.2 and 11.1 min with good baseline resolution (Rs = 1.9) on a Lux amylose-2 chiral column (250 mm × 4.0 mm, 5 microns) at ambient room temperature. The mobile phase consisted of n-hexane-ethanol-diethylamine (90:10:0.1 v/v/v) pumped at 0.9 mL/min. The eluted enantiomers were detected at 254 nm. The linear calibration curve was constructed in the range 20-1000 ng/mL for both the (S)- and (R)-enantiomers. The intra- and inter-day precision were 0.16-2.6% and 0.2-1.92% for (S)-hydroxyzine and (R)-hydroxyzine, respectively. The method was successfully applied to determine the kinetic parameters of (S)- and (R)-hydroxyzine enantiomers in rabbits. The results illustrate that the disposition of hydroxyzine enantiomers is not stereoselective in rabbits.

Multidrug toxicity involving sumatriptan.

A multidrug fatality involving sumatriptan is reported. Sumatriptan is a tryptamine derivative that acts at 5-HT(1B/1D) receptors and is used for the treatment of migraines. The decedent was a 21-year-old white female found dead in bed by her spouse. No signs of physical trauma were observed and a large number of prescription medications were discovered at the scene. Toxicological analysis of the central blood revealed sumatriptan at a concentration of 1.03 mg/L. Following therapeutic dosing guidelines, sumatriptan concentrations do not exceed 0.095 mg/L. Sumatriptan was isolated by solid-phase extraction and analyzed using liquid chromatography-tandem mass spectrometry in multiple reaction monitoring mode. A tissue distribution study was completed with the following concentrations measured: 0.61 mg/L in femoral blood, 0.56 mg/L in iliac blood, 5.01 mg/L in urine, 0.51 mg/kg in liver, 3.66 mg/kg in kidney, 0.09 mg/kg in heart, 0.32 mg/kg in spleen, 0.01 mg/kg in brain, 15.99 mg/kg in lung and 78.54 mg/45 mL in the stomach contents. Carisoprodol, meprobamate, fluoxetine, doxylamine, orphenadrine, dextromethorphan and hydroxyzine were also present in the blood at the following concentrations: 3.35, 2.36, 0.63, 0.19, 0.06, 0.55 and 0.16 mg/L. The medical examiner ruled the cause of death as acute mixed drug toxicity and the manner of death as accident.

Bilastine vs. hydroxyzine: occupation of brain histamine H1 -receptors evaluated by positron emission tomography in healthy volunteers.

AIM: A close correlation exists between positron emission tomography (PET)-determined histamine H1 -receptor occupancy (H1 RO) and the incidence of sedation. Antihistamines with H1 RO <20% are classified as non-sedating. The objective was to compare the H1 RO of bilastine, a second generation antihistamine, with that of hydroxyzine. METHODS: This randomized, double-blind, crossover study used PET imaging with [(11) C]-doxepin to evaluate H1 RO in 12 healthy males (mean age 26.2 years), after single oral administration of bilastine (20 mg), hydroxyzine (25 mg) or placebo. Binding potentials and H1 ROs were calculated in five cerebral cortex regions of interest: frontal, occipital, parietal, temporal, insula. Plasma bilastine concentrations, subjective sedation (visual analogue scale), objective psychomotor performance (digital symbol substitution test), physiological variables and safety (adverse events, AEs), were also evaluated. RESULTS: The mean binding potential of all five regions of interest (total binding potential) was significantly greater with bilastine than hydroxyzine (mean value 0.26 vs. 0.13, P < 0.01; mean difference and 95% CI -0.130 [-0.155, 0.105]). There was no significant difference between bilastine and placebo. Overall H1 RO by bilastine was significantly lower than that by hydroxyzine (mean value -3.92% vs. 53.95%, P < 0.01; mean difference and 95% CI 57.870% [42.664%, 73.075%]). There was no significant linear relationship between individual bilastine plasma concentrations and total binding potential values. No significant between-treatment differences were observed for sedation and psychomotor performance. Twenty-six non-serious AEs were reported. Sleepiness or sedation was not reported with bilastine but appeared in some subjects with hydroxyzine. CONCLUSIONS: A single oral dose of bilastine 20 mg had minimal H1 RO, was not associated with subjective sedation or objective impairment of psychomotor performance and was devoid of treatment-related sedative AEs, thus satisfying relevant subjective, objective and PET criteria as a non-sedating antihistamine.

Two-step liquid phase microextraction combined with capillary electrophoresis: a new approach to simultaneous determination of basic and zwitterionic compounds.

In this work, two-step hollow fiber-based liquid-phase microextraction procedure was evaluated for extraction of the zwitterionic cetirizine (CTZ) and basic hydroxyzine (HZ) in human plasma. In the first step of extraction, the pH of sample was adjusted at 5.0 in order to promote liquid-phase microextraction of the zwitterionic CTZ. In the second step, the pH of sample was increased up to 11.0 for extraction of basic HZ. In this procedure, the extraction times for the first and the second steps were 30 and 20 min, respectively. Owing to the high ratio between the volumes of donor phase and acceptor phase, CTZ and HZ were enriched by factors of 280 and 355, respectively. The linearity of the analytical method was investigated for both compounds in the range of 10-500 ng mL(-1) (R(2) > 0.999). Limit of quantification (S/N = 10) for CTZ and HZ was 10 ng mL(-1) , while the limit of detection was 3 ng mL(-1) for both compounds at a signal to noise ratio of 3:1. Intraday and interday relative standard deviations (RSDs, n = 6) were in the range of 6.5-16.2%. This procedure enabled CTZ and HZ to be analyzed simultaneously by capillary electrophoresis.

A fatality due to an accidental methadone substitution in a dental cocktail.

A 6-year-old male child was scheduled for a dental procedure requiring conscious sedation. Prior to the procedure, the child was administered a dental cocktail containing chloral hydrate, hydroxyzine, and methadone. After returning from the dentist, the child appeared groggy and was allowed to sleep. A few hours later, he was found unresponsive, and following resuscitation attempts at a local medical center, he was pronounced dead. Toxicological analyses of femoral blood indicated the presence of hydroxyzine at less than 0.54 µg/mL, trichloroethanol (TCE) at 8.3 µg/mL, and methadone at 0.51 µg/mL. No meperidine was detected. The cause of death was reported to be due to the toxic effects of methadone. The toxicological analysis was corroborated by the analysis of the contents of the dental cocktail, which revealed the presence of hydroxyzine, chloral hydrate, and methadone. Residue from a control sample obtained from the same pharmacy, but administered to a different subject, was found to contain hydroxyzine, chloral hydrate, and meperidine. This report represents the first known fatality due to accidental substitution of methadone in a dental cocktail.

Chiral separation and quantitation of cetirizine and hydroxyzine by maltodextrin-mediated CE in human plasma: effect of zwitterionic property of cetirizine on enantioseparation.

In the present study, a very simple CE method for chiral separation and quantitation of zwitterionic cetirizine (CTZ), as the main metabolite of hydroxyzine (HZ), and HZ has been developed. In addition, the effect of zwitterionic property of CTZ on enantioseparation was investigated. Maltodextrin, a linear polysaccharide, as a chiral selector was used and several parameters affecting the separation such as pH of BGE, concentration of chiral selector and applied voltage were studied. The best BGE conditions for CTZ and HZ enantiomers were optimized as 75 mM sodium phosphate solution at pH of 2.0, containing 5% w/v maltodextrin. Results showed that, compared to HZ, pH of BGE was an effective parameter in enantioseparation of CTZ due to the zwitterionic property of CTZ. The linear range of the method was over 30-1200 ng/mL for all enantiomers of CTZ and HZ. The quantification and detection limits (S/N=3) of all enantiomers were 30 and 10 ng/mL, respectively. The method was used to quantitative enantioseparation of CTZ and HZ in spiked human plasma.

Analytical performance evaluation of ADVIA Chemistry Carbamazepine_2 assay: minimal cross-reactivity with carbamazepine 10, 11-epoxide and none with hydroxyzine or cetirizine.

Carbamazepine is an anticonvulsant requiring routine therapeutic drug monitoring. Recently, Siemens Healthcare Diagnostic Division released a new carbamazepine assay: ADVIA Chemistry Carbamazepine_2 (Carbamazepine_2) for application on ADVIA analyzers. We evaluated the analytical performance of this assay as well as its potential cross-reactivities with carbamazepine 10, 11-epoxide, hydroxyzine, and cetirizine. The within-run and between-run precisions of the Carbamzepine-2 assay were <6% and limit of detection was 0.5 microg/ml using ADVIA 1800 analyzer. The assay was linear up to a carbamazepine concentration of 20.0 microg/ml. The new method compared well with a widely used carbamazepine EMIT 2000 assay on the Hitachi 917 analyzer. Using 75 patients' specimens (where carbamazepine concentrations varied from 0.5 to 21.7 microg/ml) and carbamazepine EMIT 2000 as the reference method (x-axis), we observed the following regression equation: y=1.04 x+0.32 (r=0.99). The new carbazepine_2 method was not affected by a hemoglobin concentration of 1,000 mg/dl, conjugated or unconjugated bilirubin concentration of 60 mg/dl, and triglyceride concentration of 1,000 mg/dl. In addition, this assay showed no cross-reactivity with hydroxyzine or cetirizine and demonstrated minimal cross-reactivity with carbamazepine 10, 11-epoxide. We conclude that the ADVIA Chemistry carbamazepine_2 assay has adequate precision and accuracy for routine therapeutic drug monitoring of carbamazepine in clinical laboratories.

Hydroxyzine and cetirizine interfere with the PENTINA carbamazepine assay but not with the ADVIA CENTEUR carbamazepine assay.

Because of a published report indicating significant interference of hydroxyzine with the particle-enhanced turbidimetric inhibition immunoassay (PENTINA) carbamazepine assay, we investigated whether such interference can be avoided by using the ADVIA Centaur carbamazepine assay. Both the Dimension Vista analyzer and ADVIA Centaur analyzer are available from Siemens Diagnostics. Aliquots of a drug-free serum pool were supplemented with various concentrations of hydroxyzine or cetirizine (0.05 microg/mL to 20 microg/mL covering therapeutic and toxic levels in serum) followed by analysis using both assays. We observed significant apparent carbamazepine concentrations using the PENTINA assay but no apparent carbamazepine level using the ADVIA Centaur assay. Because crossreactivity should be studied in the presence of the primary analyte, we also prepared a serum carbamazepine pool from patients receiving carbamazepine and then supplemented aliquots of this pool with various amounts of hydroxyzine or cetirizine followed by reanalyzing carbamazepine concentration using both assays. We observed falsely elevated carbamazepine values using the PENTINA assay but no interference was observed using the ADVIA Centaur assay. However, the falsely elevated carbamazepine values using the PENTINA assay were clinically significant at hydroxyzine or cetirizine concentrations expected in patients with severe overdoses with these drugs. We conclude that the ADVIA Centaur carbamazepine assay is free from interference of both hydroxyzine and cetirizine.

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

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).

Development of a voltammetric procedure for assay of the antihistamine drug hydroxyzine at a glassy carbon electrode: Quantification and pharmacokinetic studies.

An electrochemical study of hydroxyzine at a glassy carbon electrode was carried out in the Britton-Robinson universal buffer of pH 2-11. Hydroxyzine was oxidized in a single two-electron irreversible process controlled mainly by adsorption. A simple, sensitive and time-saving square-wave adsorptive anodic stripping voltammetric procedure has been developed for determination of hydroxyzine in its commercial tablets and human serum without prior extraction. The optimized procedural conditions were: frequency=120Hz, scan increment=10mV, pulse-amplitude=25mV, accumulation potential=-0.3V, accumulation time=90-300s and a Britton-Robinson universal buffer of pH 4 as a supporting electrolyte. Mean recoveries of 100.5+/-0.71 and 98.6+/-1.12% (n=5) were achieved for assay of hydroxyzine in Atarax 10 and 25mg dosage forms, respectively. Limit of detection of 1.5x10(-8)molL(-1) (5.624ngmL(-1)) and limit of quantitation of 5.0x10(-8)molL(-1) (18.746ngmL(-1)) were achieved in human serum with a mean recovery of 98.4+/-1.22%, without prior extraction of the drug. Moreover, the described procedure was applied for evaluating the pharmacokinetic parameters of hydroxyzine in plasma of two healthy volunteers after administration of a single oral dose (Atarax)-25mg).

Precolumn fluorescence labeling method for simultaneous determination of hydroxyzine and cetirizine in human serum.

A highly selective and sensitive method was developed for simultaneous determination of the antihistaminic drug hydroxyzine (HZ) and its pharmacologically active metabolite cetirizine (CZ) in human serum using haloperidol as internal standard. The method was based on fluorescence labeling of both drugs with a fluorescent arylboronic acid 4-(4,5-diphenyl-1H-imidazol-2-yl)phenyl boronic acid followed by separation on silica column using a mobile phase consisting of acetonitrile and water (90:10, v/v%) containing triethylamine and acetic acid. The labeling reaction conditions were optimized and the liquid-liquid extraction method was successfully applied to extract the both drugs from serum. The linearity range was 0.025-2.00 microg/mL for HZ and CZ. The limit of detection (S/N = 3) was 10 and 5 ng/mL for HZ and CZ, respectively.

False-positive serum tricyclic antidepressant concentrations using fluorescence polarization immunoassay due to the presence of hydroxyzine and cetirizine.

A recent report indicates that hydroxyzine and its active metabolite cetirizine interfere with the PENTINA carbamazepine assay. The potential interference of hydroxyzine and cetirizine with the fluorescence polarization immunoassay (FPIA) and CEDIA assay of carbamazepine as well as with the fluorescence polarization immunoassay of tricyclic antidepressants (TCA) was studied. Aliquots of drug-free serum pools were supplemented with various concentrations of hydroxyzine and cetirizine representing therapeutic, mild to moderate toxic as well as very toxic concentrations. Then apparent carbamazepine and TCA concentrations were measured by immunoassays. Although no interference of hydroxyzine and cetirizine was observed with carbamazepine assays (FPIA and CEDIA), significant apparent TCA concentrations were observed when aliquots of drug-free serum were supplemented with hydroxyzine or cetirizine. Mathematical formula was devised to predict hydroxyzine and/or cetirizine concentration in serum based on observed apparent TCA levels. Hydroxyzine and cetirizine also falsely increased total TCA values when aliquots of serum pool prepared from patients receiving TCA were further supplemented with these drugs. In conclusion, hydroxyzine and cetirizine do not interfere with the FPIA and CEDIA carbamazepine assays but interfere with the measurement of total TCA using the FPIA.

Evaluation of the cognitive, psychomotor and pharmacokinetic profiles of rupatadine, hydroxyzine and cetirizine, in combination with alcohol, in healthy volunteers.

INTRODUCTION: The Central Nervous System (CNS) impairment induced by moderate alcohol (ALC) ingestion may be enhanced if other drugs are taken simultaneously. Rupatadine (RUP) is a new H(1)-antihistamine which also inhibits platelet activating factor (PAF) release in inflammatory reactions. OBJECTIVE: The main aim of the study was to assess the effects of ALC 0.8 g/Kg on RUP (10 mg and 20 mg) CNS effects. An evaluation of alcohol and RUP pharmacokinetics was also attained. METHODS: Eighteen healthy young volunteers of both sexes participated in a phase I, randomised, crossover, double-blind, placebo-controlled study. At 2-week intervals they received six treatments: (a) placebo (PLA), (b) ALC alone and ALC in combination with: (c) hydroxyzine 25 mg (HYD), (d) cetirizine 10 mg (CET), (e) RUP 10 mg or (f) RUP 20 mg. At baseline and several times thereafter, seven psychomotor performance tests (finger tapping, fine motoric skills, nystagmus, temporal estimation, critical-flicker-fusion frequency, 'd2' cancellation, simple reaction) and eleven subjective self-reports (drunkenness, sleepiness, alertness, clumsiness, anger, inattentiveness, efficiency, happiness, hostility, interest and extraversion) were carried out. Two-way (treatment, time) ANOVAs for repeated measures to each variable together with a multivariate non-parametric approach were applied. Plasma concentrations of alcohol, and of RUP and its metabolites, were quantified by validated immunofluorescence and LC/MS/MS methods, respectively. Plasma-time curves for all compounds were analysed by means of model-independent methods. RESULTS: The combination of alcohol with HYD, CET and RUP 20 mg produced more cognitive and psychomotor impairment as compared to alcohol alone, being the combination of alcohol and HYD the one which induced the greatest deterioration. The combination of alcohol and RUP 10 mg could not be differentiated from ALC alone. Subjective self-reports reflect effects on metacognition after the combination of alcohol with HYD and CET i.e. the increased objective impairment observed was not subjectively perceived by the subjects. No significant differences were obtained when comparing alcohol plasma concentrations assessed after the treatments evaluated. RUP showed a lineal kinetic relationship after 10 and 20 mg with a higher exposition to both metabolites assayed. CONCLUSIONS: Present results showed that single oral doses of rupatadine 10 mg in combination with alcohol do not produce more cognitive and psychomotor impairment than alcohol alone. Higher doses of rupatadine, in combination with alcohol, may induce cognitive and psychomotor deterioration as hydroxyzine and cetirizine at therapeutic doses.

Neonatal seizures associated with maternal hydroxyzine hydrochloride in late pregnancy.

This is the first report of a neonatal withdrawal syndrome associated with maternal hydroxyzine treatment (150 mg/day) confirmed by measurements of hydroxyzine plasma concentrations in the mother and infant after birth. Hydroxyzine plasma concentrations were measured by liquid chromatography-mass spectrometry. Neurological symptoms with low neonatal concentrations of hydroxyzine may be due to a withdrawal syndrome. According to previous observations and this case report, clinicians should be warned of this possible rare neurological complication of hydroxyzine in neonates born from long term treated mothers.

Hydroxyzine and metabolites as a source of interference in carbamazepine particle-enhanced turbidimetric inhibition immunoassay (PETINIA).

A 32-year-old epileptic patient with a lengthy history of multiple-drug abuse and psychotic disorders was found to have an elevated serum carbamazepine concentration of 40.5 mg/L (therapeutic range 4-12 mg/L) using particle-enhanced turbidimetric inhibition immunoassay (PETINIA). Serum reanalysis by LC-DAD revealed only high hydroxyzine (HDZ) concentration (HDZ = 0.55 mg/L; therapeutic range <0.1 mg/L), suggesting cross-reactivity between HDZ and PETINIA. To confirm this hypothesis, the authors tested 2 commercially available carbamazepine immunoassays, PETINIA and EMIT 2000, for in vitro cross-reactivity with HDZ and 2 HDZ metabolites (cetirizine and norchlorcyclizine). To determine the frequency of this interaction in a clinical setting, 40 sera of 39 patients taking HDZ without carbamazepine were tested by both immunoassays. For some samples, LC-ESI-MS analysis of HDZ metabolites was performed. Additionally, cross-reactivities produced by other benzhydrylpiperazine drugs were evaluated. in vitro, 5 mg of HDZ, cetirizine, and norchlorcyclizine cross-reacted with PETINIA at 85%, 125%, and 66%, respectively. Conversely, EMIT 2000 showed no cross-reactivity. For PETINIA, erroneous carbamazepine concentrations were detected in 35 out of 40 sera of patients taking HDZ. The magnitude of interference correlated moderately with serum HDZ concentrations (Spearman rho coefficient 0.58, P < 0.001), suggesting a major role for the multiple HDZ metabolites (4 serum metabolites were detected by LC-ESI-MS). Furthermore, other benzhydrylpiperazine drugs (eg, oxatomide) showed in vitro cross-reactivity with PETINIA. In conclusion, HDZ and its metabolites cross-react with carbamazepine PETINIA immunoassay, which could significantly affect the correct interpretation of serum carbamazepine concentrations in patients treated with HDZ.

A simple high-performance liquid chromatographic method for detection of hydroxyzine in human plasma after overdose.

INTRODUCTION: Hydroxyzine, a piperazine H1-receptor antagonist, is effective in generalised anxiety disorder. For toxicological purposes, a simple reversed-phase high-performance liquid chromatographic assay was developed for the detection of hydroxyzine in human plasma. METHODS: A liquid-liquid procedure was used to extract the drug from plasma in the presence of an internal standard (clothiapine). The analysis was performed on a Spherisorb S5 C(8) analytical column with UV detection. RESULTS: A linear response was observed over the concentration range 20-1500 ng/ml. A good accuracy (bias<7.3%) was achieved for all quality controls, with intraday and interday variation coefficients inferior to 8.5%. The limit of detection was 10 ng/ml, without interference of endogenous components. DISCUSSION: This rapid method (run time<13 min) is currently used for poison management involving hydroxyzine.

P-glycoprotein influences the brain concentrations of cetirizine (Zyrtec), a second-generation non-sedating antihistamine.

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.

Distribution of antihistamines into the CSF following intranasal delivery.

The preferential absorption of certain drug compounds from the nasal cavity into the cerebrospinal fluid (CSF) raises questions regarding the transport processes controlling drug disposition following intranasal delivery. The disposition characteristics of several structurally similar antihistamine compounds, hydroxyzine, chlorpheniramine, triprolidine, and chlorcyclizine, into the CSF following nasal administration were studied using the rat as an animal model. The antihistamines were administered either intranasally or intra-arterially, and serial CSF and plasma samples were collected from the cisterna magna and the femoral artery, respectively. The drug levels in CSF and plasma were assayed by HPLC. Hydroxyzine concentrations in plasma and CSF were found to be significantly greater than most of the other compounds tested. In addition, hydroxyzine also showed the most rapid systemic absorption following nasal administration. Interestingly, the hydroxyzine levels in CSF following intranasal administration were significantly higher than those following intra-arterial administration. The AUC ratios between CSF and plasma for hydroxyzine after intranasal and intra-arterial administration were 4.0 and 0.4, respectively. The AUC ratios for triprolidine, the other antihistamine with measurable CSF concentrations, were 0.5 and 0.7, respectively. The distribution of antihistamines from the nasal membrane into the CSF appears to be controlled by a combination of their molecular properties. It also appears that the intranasal delivery of drugs with optimal physicochemical characteristics can result in an improved CNS bioavailability compared to those achieved from an equivalent parenteral dose.