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.

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.

Microencapsulation of hydroxyzine HCl by thermal phase separation: in vitro release enhancement and in vivo pharmacodynamic evaluation.

The systemic effect of hydroxyzine hydrochloride following its oral administration or topical application is associated with non compliant anticholinergic effect. Subsequently, the present study aims to prepare microcapsules loaded with hydroxyzine hydrochloride enabling its controlled release into the skin and reducing the side effect of its systemic absorption. The microcapsules were prepared by thermal phase separation method using ethyl cellulose/cyclohexane. Optimization of the formulation parameters was carried out by: (1) varying the type and the concentration of the coacervation inducer with microcapsules prepared with three different core: wall ratios, (2) by using ethyl cellulose with two different viscosities, (3) and by the addition of pore inducers such as pregelatinized starch and sucrose in order to enhance the drug release. Microcapsules of 99% encapsulation efficiency were prepared using 1% w/v polyisobutylene, and 1:0.1 core: wall ratio. The highest percent of drug is released after 9 h from microcapsules prepared using 1:0.1 core :wall ratio. Almost 100% drug was released after 3 h, from the same microcapsules prepared with pregelatinized starch that acts as a core coated with the drug. The pharmacodynamic effect of the chosen preparation was tested on the shaved back of histamine sensitized rabbits. Histopathological studies were driven for the detection of the healing of inflamed tissues.

In vitro and in vivo evaluation of hydroxyzine hydrochloride microsponges for topical delivery.

Hydroxyzine HCl is used in oral formulations for the treatment of urticaria and atopic dermatitis. Dizziness, blurred vision, and anticholinergic responses, represent the most common side effects. It has been shown that controlled release of the drug from a delivery system to the skin could reduce the side effects while reducing percutaneous absorption. Therefore, the aim of the present study was to produce an effective drug-loaded dosage form that is able to control the release of hydroxyzine hydrochloride into the skin. The Microsponge Delivery System is a unique technology for the controlled release of topical agents, and it consists of porous polymeric microspheres, typically 10-50 µm in diameter, loaded with active agents. Eudragit RS-100 microsponges of the drug were prepared by the oil in an oil emulsion solvent diffusion method using acetone as dispersing solvent and liquid paraffin as the continuous medium. Magnesium stearate was added to the dispersed phase to prevent flocculation of Eudragit RS-100 microsponges. Pore inducers such as sucrose and pregelatinized starch were used to enhance the rate of drug release. Microsponges of nearly 98% encapsulation efficiency and 60-70% porosity were produced. The pharmacodynamic effect of the chosen preparation was tested on the shaved back of histamine-sensitized rabbits. Histopathological studies were driven for the detection of the healing of inflamed tissues.

The Role of Alcohol Dehydrogenase in Drug Metabolism: Beyond Ethanol Oxidation.

Alcohol dehydrogenases (ADHs) are most known for their roles in oxidation and elimination of ethanol. Although less known, ADHs also play a critical role in the metabolism of a number of drugs and metabolites that contain alcohol functional groups, such as abacavir (HIV/AIDS), hydroxyzine (antihistamine), and ethambutol (antituberculosis). ADHs consist of 7 gene family numbers and several genetic polymorphic forms. ADHs are cytosolic enzymes that are most abundantly found in the liver, although also present in other tissues including gastrointestinal tract and adipose. Marked species differences exist for ADHs including genes, proteins, enzymatic activity, and tissue distribution. The active site of ADHs is relatively small and cylindrical in shape. This results in somewhat narrow substrate specificity. Secondary alcohols are generally poor substrates for ADHs. In vitro-in vivo correlations for ADHs have not been established, partly due to insufficient clinical data. Fomepizole (4-methylpyrazole) is a nonspecific ADH inhibitor currently being used as an antidote for the treatment of methanol and ethylene glycol poisoning. Fomepizole also has the potential to treat intoxication of other substances of abuse by inhibiting ADHs to prevent formation of toxic metabolites. ADHs are inducible through farnesoid X receptor (FXR) and other transcription factors. Drug-drug interactions have been observed in the clinic for ADHs between ethanol and therapeutic drugs, and between fomepizole and ADH substrates. Future research in this area will provide additional insights about this class of complex, yet fascinating enzymes.

Anticholinergic Load and Nutritional Status in Older Individuals.

OBJECTIVES: The association between anticholinergic load-based Anticholinergic Risk Scale scores and nutritional status is unclear in Japanese patients. The aim of this study was to establish whether anticholinergic load affects the nutritional status of geriatric patients in convalescent stages. DESIGN: Retrospective longitudinal cohort study. SETTING: Convalescent rehabilitation wards. PARTICIPANTS: Of the 1490 patients aged ≥65 years who were discharged from convalescent rehabilitation wards between July 2010 and October 2018, 908 patients met the eligibility criteria. They were categorized according to the presence or absence of increased anticholinergic load from admission to discharge. MEASUREMENTS: Demographic data, laboratory data, the Functional Independence Measure were analyzed between the groups. The primary outcome was Geriatric Nutritional Risk Index (GNRI) at discharge. Multiple linear regression analysis was performed to analyze the relationship between anticholinergic load and GNRI at discharge. RESULTS: Multiple linear regression analysis after adjusting for confounding factors revealed that anticholinergic load was independently and negatively correlated with GNRI at discharge. Particularly, the use of chlorpromazine, hydroxyzine, haloperidol, metoclopramide, risperidone, etc. increased significantly from admission to discharge. CONCLUSION: Increased anticholinergic load during hospitalization may be a predictor of nutritional status in geriatric patients.

Physicochemical, pharmacological and pharmacokinetic properties of the zwitterionic antihistamines cetirizine and levocetirizine.

Cetirizine, marketed as a racemic mixture containing both levocetirizine and dextrocetirizine, is a member of the second generation H(1) antihistamines clinically used for the treatment of symptoms associated with seasonal allergic rhinitis. Recently, its single R-enantiomer levocetirizine has been approved by the FDA as the newest antihistamine. Cetirizine is a piperazine derivative related to the first generation H(1) antagonist hydroxyzine, and is the major metabolite in the blood circulation after hydroxyzine administration in humans. The acid functionality of cetirizine in combination with one of the basic nitrogens of piperazine ring makes this compound a very unique zwitterion. The molecular structure of cetirizine allows its carboxylic group to interact with the basic nitrogen via folded conformers, therefore, it possesses relatively high lipophilicity at physiological pH (LogD=1.5). While both cetirizine and hydroxyzine possess high affinity at the H(1) receptor, the R-configured levocetirizine has much slower dissociation rate from the H(1) receptor than R-hydroxyzine, making it an insurmountable antagonist. In addition, the pharmacokinetics of cetirizine significantly differs from those of the basic and lipophilic hydroxyzine. For example, cetirizine has much lower CNS penetration than hydroxyzine, which may be explained by the zwitterionic structure of cetirizine and its P-glycoprotein activity. Cetirizine exhibits high intestinal absorption in humans and its oral bioavailability is estimated to be greater than 70%. Very importantly, cetirizine, especially levocetirizine, has a negligible interaction with the liver enzymes, and is mainly excreted in the urine as the parent despite its high plasma protein binding (88 approximately 96%). The recommended dose of levocetirizine is 5 mg once daily, while its pharmacokinetic half-life is about 7 h in humans. This review will focus on the physicochemical, pharmacological and pharmacokinetic properties of cetirizine and levocetirizine in comparison with those of hydroxyzine. The zwitterionic cetirizine displays distinct advantages over the basic hydroxyzine in several categories such as slow receptor dissociation rate, high selectivity, negligible liver enzyme interaction and low CNS penetration. Therefore, cetirizine, or its single isomer levocetirizine, might serve a good example for medicinal chemists to design zwitterionic drugs from a basic, acidic or neutral lead molecule for peripheral biological targets.

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).

Inhibition of amine oxidases by the histamine-1 receptor antagonist hydroxyzine.

The effects of the drug hydroxyzine on the activities of the rat liver monoamine oxidases (EC 1.4.3.6; MAO) and the membrane-bound and soluble forms of bovine semicarbazide-sensitive amine oxidase (EC 1.4.3.6; SSAO) were studied. Hydroxyzine was found to be a competitive inhibitor of MAO-B (Ki - 38 microM), whereas it had a low potency towards MAO-A (IC50 > 630 microM). Although it was a relatively potent competitive inhibitor of bovine plasma SSAO (Ki approximately 1.5 microM), it was a weak inhibitor of the membrane-bound form of the enzyme from bovine lung (IC50 approximately 1 mM). These findings extend our knowledge of the drug binding capabilities of the amine oxidases and suggest that these interactions may contribute to the complex actions of this drug.

Transport of hydroxyzine and triprolidine across bovine olfactory mucosa: role of passive diffusion in the direct nose-to-brain uptake of small molecules.

Hydroxyzine and triprolidine have both been reported to reach the CNS following nasal administration. The objective of this study was to investigate their in vitro permeation across bovine olfactory mucosa in order to further characterize the biological and physicochemical parameters that influence direct nose-to-brain transport. In vitro experiments were conducted using Sweetana-Grass (Navicyte) vertical diffusion cells to evaluate the effect of directionality, donor concentration and pH on the permeation of hydroxyzine and triprolidine across excised bovine olfactory mucosa. These studies demonstrated that the Jm-s (mucosal-submucosal flux) and Js-m (submucosal-mucosal flux) of hydroxyzine and triprolidine across the olfactory mucosa were linearly dependent upon the donor concentration without any evidence of saturable transport. Hydroxyzine inhibited the efflux of P-gp substrates like etoposide and chlorpheniramine across the olfactory mucosa. Both hydroxyzine and triprolidine reduced the net flux (Js-m-Jm-s) of etoposide with IC50 values of 39.2 and 130.6 microM, respectively. The lipophilicty of these compounds, coupled with their ability to inhibit P-gp, enable them to freely permeate across the olfactory mucosa. Despite the presence of a number of protective barriers such as efflux transporters and metabolizing enzymes in the olfactory system, lipophilic compounds such as hydroxyzine and triprolidine can access the CNS primarily by passive diffusion when administered via the nasal cavity.

Pharmacokinetic and pharmacodynamic studies of the H1-receptor antagonist hydroxyzine in the elderly.

The pharmacokinetics and pharmacodynamics of the antipruritic H1-receptor antagonist hydroxyzine hydrochloride were studied in nine healthy, fasting subjects (mean age 69.5 +/- 3.7 years) who ingested a single dose of hydroxyzine syrup, 0.7 mg/kg (mean dose 49.0 +/- 6.7 mg). Blood samples were collected hourly for 6 hours, every 2 hours from 6 to 12 hours, at 24 hours, and then every 24 hours for 144 hours. At these times an intradermal injection of 0.01 ml of a 0.1 mg/ml histamine phosphate solution was performed, and wheal and flare areas were computed. The serum elimination t1/2 of hydroxyzine was 29.3 +/- 10.1 hours; the volume of distribution was 22.5 +/- 6.3 L/kg; the clearance rate was 9.6 +/- 3.2 ml/min/kg, and the AUC was 1383.1 +/- 1039.0 ng.hr/ml. The mean serum elimination t1/2 of cetirizine, the active metabolite of hydroxyzine generated in vivo, was 24.8 +/- 7.7 hours, not significantly different from that of the parent compound (p = 0.05). After a single dose of hydroxyzine the mean wheal and flare areas were significantly suppressed from 1 to 144 hours, compared with the mean predose wheal and flare sizes (p less than 0.01). Maximum wheal suppression, compared with all other wheals measured during the study, occurred from 4 to 10 hours, inclusive, and maximum flare suppression occurred from 2 to 72 hours, inclusive (p less than 0.01). Hydroxyzine has a long t1/2 and a large volume of distribution in the elderly. The suppressive effect on the wheal and flare after a single dose of hydroxyzine is also extremely prolonged, suggesting the possibility of enhanced H1-receptor activity in old age.

Cetirizine. A review of its pharmacological properties and clinical potential in allergic rhinitis, pollen-induced asthma, and chronic urticaria.

Cetirizine, a piperazine derivative and carboxylated metabolite of hydroxyzine, is a potent histamine H1-receptor antagonist with antiallergic properties. It has marked affinity for peripheral histamine H1-receptors and, at the standard dose of 10mg daily, lacks the CNS depressant effects of standard antihistamines. In addition, it inhibits histamine release and eosinophil chemotaxis during the secondary phase of the allergic response. Results from controlled clinical trials indicate that cetirizine is an effective and well tolerated treatment of seasonal and perennial allergic rhinitis and chronic idiopathic urticaria. Cetirizine appears to be as effective as conventional dosages of terfenadine, chlorpheniramine and hydroxyzine in relieving symptoms associated with these disorders and produces a markedly lower incidence of sedation than chlorpheniramine, hydroxyzine and several other standard antihistamines. Thus, cetirizine appears to provide a useful alternative to other 'nonsedating' antihistamines; cetirizine may also have a future role in the treatment of allergic asthma and certain forms of physical urticaria.

The pharmacokinetics and pharmacodynamics of hydroxyzine in patients with primary biliary cirrhosis.

Hydroxyzine, a potent H1-receptor antagonist often used for relief of pruritus in patients with hepatic dysfunction, was studied in eight patients, mean age 53.4 +/- SD 11.2 years, with primary biliary cirrhosis. The patients ingested a single dose of hydroxyzine, 0.7 mg/kg (mean dose 43.9 +/- 6.6 mg). Before the dose, then hourly for 6 hours, every 2 hours from 6-12 hours, at 24 hours, and every 24 hours for 6 days, serum hydroxyzine and cetirizine were measured and an intradermal injection of 0.01 mL of a 0.1 mg/mL solution of histamine phosphate was performed. Wheals and flares were traced at 10 minutes and the areas were calculated. Mean peak hydroxyzine levels of 116.5 +/- 60.6 ng/mL occurred at 2.3 +/- 0.7 hours and mean peak cetirizine levels of 500.4 +/- 302.0 ng/mL occurred at 4.8 +/- 2.8 hours. The mean serum elimination half-life of hydroxyzine was 36.6 +/- 13.1 hours, and the mean serum elimination half-life of cetirizine was 25.0 +/- 8.2 hours. The mean hydroxyzine clearance rate was 8.65 +/- 7.46 mL/min/kg, and the mean volume of distribution was 22.7 +/- 13.3 L/kg. The mean wheal area was suppressed (P less than 0.01) from 1 to 120 hours, with maximal suppression from 2 to 48 hours. The mean flare area was suppressed from 1 to 144 hours, with maximal suppression from 3 to 24 hours (P less than 0.01). All patients became sleepy from 0.5 to 6 hours. Blurred vision, dizziness and dry mouth each occurred in two patients. Hydroxyzine elimination is impaired in patients with primary biliary cirrhosis.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Hydroxyzine from topical phospholipid liposomal formulations: evaluation of peripheral antihistaminic activity and systemic absorption in a rabbit model.

Hydroxyzine, an effective but sedating H1-antihistamine is given orally to treat allergic skin disorders. This study was performed to assess the peripheral H(1)-antihistaminic activity and extent of systemic absorption of hydroxyzine from liposomes applied to the skin. Using L-alpha-phosphatidylcholine (PC), small unilamellar vesicles (SUVs) and multilamellar vesicles (MLVs) containing hydroxyzine were prepared. Hydroxyzine in Glaxal Base (GB) was used as the control. Using a randomized, crossover design, each formulation, containing 10 mg of hydroxyzine, was applied to the shaved backs of 6 rabbits (3.08 +/- 0.05 kg). Histamine-induced wheal tests and blood sampling were performed at designated time intervals up to 24 hours. Compared with baseline, hydroxyzine from all formulations significantly suppressed histamine-induced wheal formation by 75% to 95% for up to 24 hours. Mean maximum suppression, 85% to 94%, occurred from 2 to 6 hours, with no differences among the formulations. The areas of plasma hydroxyzine concentration versus time area under the curve (AUCs) from PC-SUV and PC-MLV, 80.1 +/- 20.8 and 78.4 +/- 33.9 ng/mL/h, respectively, were lower than that from GB, 492 +/- 141 ng/mL/h (P < or =.05) over 24 hours. Plasma concentrations of cetirizine arising in-vivo as the active metabolite of hydroxyzine, from PC-SUV, PC-MLV, and GB, were similar with AUCs of 765 +/- 50, 1035 +/- 202, and 957 +/- 227 ng/mL/h, respectively (P < or =.05). Only 0.02% to 0.06% of the initial hydroxyzine dose remained on the skin after 24 hours. In this model, hydroxyzine from SUV and MLV had excellent topical H1-antihistaminic activity, and minimal systemic exposure occurred. Cetirizine formed in-vivo contributed to some of H1-antihistaminic activity.

Single dose pharmacokinetics of cetirizine in young and elderly volunteers.

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.

The second-generation antihistamines. What makes them different?

Physicians often are faced with the decision of whether to prescribe a drug for its positive therapeutic effects or avoid prescribing it because of unacceptable side effects. This dilemma can sometimes be eased by keeping current on new therapeutic options as they become available. The authors provide a useful update on the state of the art in antihistamine therapy.

Hydroxyzine distribution in postmortem cases and potential for redistribution.

Hydroxyzine is an antihistaminic with sedative properties used in the control of anxiety and emesis. Peripheral blood hydroxyzine concentrations are compared to central blood and liver concentrations in 10 medical examiner cases. Specimens were initially screened for alcohol and simple volatiles by GC-FID headspace analysis, ELISA for drugs of abuse, and alkaline drugs by GC/MS. Hydroxyzine, when detected by the alkaline drug screen, was subsequently confirmed and quantified by a specific GC-NPD procedure. Data suggest that postmortem peripheral blood hydroxyzine concentrations may be considered therapeutic to at least 0.24 mg/L and corresponding liver concentrations to at least 4.9 mg/kg. Hydroxyzine concentrations ranged 0.07-3.0mg/L in peripheral blood, 0.04-3.8 mg/L in central blood, and 0.88-55 mg/kg in liver. Hydroxyzine central blood to peripheral blood ratios averaged 0.92±0.25 (±standard deviation; N=6). Liver to peripheral blood ratios, on the other hand, were higher and averaged 13.8±6.2 (±standard deviation; N=10). Given that a liver to peripheral blood ratio less than 5 is consistent with little to no postmortem redistribution while exceeding 20-30 is indicative of propensity for significant postmortem redistribution, these data suggest that hydroxyzine is prone to a moderate degree of postmortem redistribution.

Understanding the pharmacokinetics of anxiolytic drugs.

INTRODUCTION: Anxiety disorders are considered the most common mental disorders and they can increase the risk for comorbid mood and substance use disorders, significantly contributing to the global burden of disease. For this reason, anxiolytics are the most prescribed psychoactive drugs, particularly in the Western world. AREAS COVERED: This review aims to analyze pharmacokinetic profile, plasma level variations so as the metabolism, interactions and possible relation to clinical effect of several drugs which are used primarily as anxiolytics. The drugs analyzed include benzodiazepines, anticonvulsants (pregabalin, gabapentin), buspirone, ß-blockers and antihistamines (hydroxyzine). Regarding the most frequently used anxiolytic benzodiazepines, data on alprazolam, bromazepam, chlordesmethyldiazepam, chlordiazepoxide, clotiazepam, diazepam, etizolam, lorazepam, oxazepam, prazepam and clonazepam have been detailed. EXPERT OPINION: There is a need for a more balanced assessment of the benefits and risks associated with benzodiazepine use, particularly considering pharmacokinetic profile of the drugs to ensure that patients, who would truly benefit from these agents, are not denied appropriate treatment. An optimal pharmacological approach involving an integrative pharmacokinetic and pharmacodynamic optimization strategy would ensure better treatment and personalization of anxiety disorders. So it would be desirable for the development of new anxiolytic drug(s) that are more selective, fast acting and free from the unwanted effects associated with the traditional benzodiazepines as tolerance or dependence.

Triprotic acid-base microequilibria and pharmacokinetic sequelae of cetirizine.

(1)H NMR-pH titrations of cetirizine, the widely used antihistamine and four related compounds were carried out and the related 11 macroscopic protonation constants were determined. The interactivity parameter between the two piperazine amine groups was obtained from two symmetric piperazine derivatives. Combining these two types of datasets, all the 12 microconstants and derived tautomeric constants of cetirizine were calculated. Upon this basis, the conflicting literature data of cetirizine microspeciation were clarified, and the pharmacokinetic absorption-distribution properties could be interpreted. The pH-dependent distribution of the microspecies is provided.