Aphthasol
P-glycoprotein limits the brain penetration of nonsedating but not sedating H1-antagonists.

Chen C, Hanson E, Watson JW, Lee JS.

Pfizer Global Research and Development, Pfizer Inc., Groton, Connecticut 06340, USA. cuiping_chen groton.pfizer.com

The present study evaluates the impact of P-glycoprotein (P-gp) on plasma-brain disposition and transepithelial transport of sedating versus nonsedating H1-antagonists using multidrug-resistant (mdr) gene 1a and 1b (mdr1a/b) knockout (KO) mice and human MDR1-transfected Madin-Darby canine kidney (MDCK) cells. Three nonsedating (cetirizine, loratadine, and desloratadine) and three sedating (diphenhydramine, hydroxyzine, and triprolidine) H1-antagonists were tested. Each compound was administered to KO and wild-type (WT) mice intravenously at 5 mg/kg. Plasma and brain drug concentrations were determined by liquid chromatography-mass spectrometry analysis. Mean pharmacokinetic parameters (CL, V(ss), and t(1/2)) were obtained using WinNonlin. In addition, certirizine, desloratadine, diphenhydramine, and triprolidine (2 microM) were tested as substrates for MDR1 using MDR1-MDCK cells. The bidirectional apparent permeability was determined by measuring the amount of compound at the receiving side at 5 h. The brain-to-plasma area under the curve (AUC) ratio was 4-, 2-, and >14-fold higher in KO compared with WT mice for cetirizine, loratadine, and desloratadine, respectively. In contrast, the brain-to-plasma AUC ratio between KO and WT was comparable for hydroxyzine, diphenhydramine, and triprolidine. Likewise, the efflux ratio between basolateral to apical and apical to basolateral was 4.6- and 6.6-fold higher in MDR1-MDCK than the parental MDCK for certirizine and desloratadine, respectively, whereas it was approximately 1 for diphenhydramine and triprolidine. Our results demonstrate that sedating H1-antagonists hydroxyzine, diphenhydramine, and triprolidine are not P-gp substrates. In contrast, nonsedating H1-antagonists cetirizine, loratadine, and desloratadine are P-gp substrates. Affinity for P-gp at BBB may explain the lack of central nervous system side effects of modern H1-antagonists.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12584158&dopt=Abstract hydroxyzine Atarax



Aphthasol
Quantitative enantiomeric analysis of chlorcyclizine, hydroxyzine, and meclizine by capillary electrophoresis.

Ho Y, Wu H, Wu S, Chen S, Kou H.

Graduate Institute of Pharmaceutical Sciences, Kaohsiung Medical University, 807, Kaohsiung, Taiwan.

A simple capillary zone electrophoresis method was developed for the quantitative enantiomeric analysis of piperazine antihistamines with teratogenic suspicion in animals. Enantioseparation of chlorcyclizine, hydroxyzine, and meclizine was performed in glycine buffer (0.6 mol L(-1); pH 3.00) with sulfated beta-cyclodextrin (5 mg mL(-1)) as a chiral selector; and the separated drugs were monitored by ultra-violet detector. The lower quantitation of the individual enantiomer is attainable at 10 micro mol L(-1), using an achiral piperazine drug (cyclizine) as internal standard. The method is simple and rapid with a short run time (<5 min) for the analysis of chlorcyclizine, hydroxyzine or meclizine enantiomers.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12830360&dopt=Abstract hydroxyzine Atarax



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

Polli JW, Baughman TM, Humphreys JE, Jordan KH, Mote AL, Salisbury JA, Tippin TK, Serabjit-Singh CJ.

Preclinical Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Inc., P.O. Box 13398, Room: MAI.2213.2G, Research Triangle Park, North Carolina 27709, USA. joseph.w.polli gsk.com

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. Copyright 2003 Wiley-Liss, Inc. and the American Pharmacists Association

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14502547&dopt=Abstract hydroxyzine Atarax



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

Elzainy AA, Gu X, Simons FE, Simons KJ.

Faculty of Pharmacy, University of Manitoba, Winnipeg, Canada.

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.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15198516&dopt=Abstract hydroxyzine Atarax



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

Pehourcq F.

Department of Clinical Pharmacology and Toxicology, CHU Pellegrin, Place Amelie Raba-Leon, 33076 Bordeaux Cedex, France. fabienne.pehourcq chu-bordeaux.fr

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.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15233966&dopt=Abstract hydroxyzine Atarax