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Table of Contents
Vol. 72, No. 2, 2004
Issue release date: October 2004
Section title: Original Paper
Pharmacology 2004;72:92–98
(DOI:10.1159/000079137)

Steady-State Brain Concentrations of Antihistamines in Rats

Doan K.M.a · Wring S.A.a · Shampine L.J.a · Jordan K.H.a · Bishop J.P.a · Kratz J.b · Yang E.b · Serabjit-Singh C.J.a · Adkison K.K.a · Polli J.W.a
aPreclinical Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, N.C., and bPreclinical Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pa., USA

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Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: January 05, 2004
Accepted: March 16, 2004
Published online: September 01, 2004
Issue release date: October 2004

Number of Print Pages: 7
Number of Figures: 1
Number of Tables: 3

ISSN: 0031-7012 (Print)
eISSN: 1423-0313 (Online)

For additional information: http://www.karger.com/PHA

Abstract

The purpose of this study was to measure the in vivo brain distribution of antihistamines and assess the influence of in vitro permeability, P-glycoprotein (Pgp) efflux, and plasma protein binding. Six antihistamines (acrivastine, chlorpheniramine, diphenhydramine doxylamine, fexofenadine, terfenadine) were selected based on previously reported in vitro permeability and Pgp efflux properties and dosed intravenously to steady-state plasma concentrations of 2–10 µmol/l in rats. Plasma and brain concentrations were measured by LC/MS/MS, and protein binding determined by ultrafiltration. Doxylamine, diphenhydramine and chlorpheniramine had brain-to-plasma concentration ratios of 4.34 ± 1.26, 18.4 ± 2.35 and 34.0 ± 9.02, respectively. These drugs had high passive membrane permeability (>310 nm/s), moderate protein binding (71–84%) and were not Pgp substrates; features that yield high CNS penetration. In contrast, acrivastine and fexofenadine had low brain-to-plasma ratios of 0.072 ± 0.014 and 0.018 + 0.002, consistent with low passive membrane permeability for both compounds (16.2 and 66 nm/s, respectively) and Pgp efflux. Finally, terfenadine had a brain-to-plasma ratio of 2.21 ± 1.00 even though it underwent Pgp-mediated efflux (in vitro ratio = 2.88). Terfenadine’s high passive permeability (285 nm/s) overcame the Pgp-mediated efflux to yield brain-to-plasma ratio >1. The brain-to-unbound plasma ratio was 22-fold higher suggesting that protein binding (96.3% bound) limited terfenadine’s brain distribution. In conclusion, passive membrane permeability, Pgp-mediated efflux and/or high plasma protein binding influence the in vivo brain distribution of antihistamine drugs.

© 2004 S. Karger AG, Basel


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: January 05, 2004
Accepted: March 16, 2004
Published online: September 01, 2004
Issue release date: October 2004

Number of Print Pages: 7
Number of Figures: 1
Number of Tables: 3

ISSN: 0031-7012 (Print)
eISSN: 1423-0313 (Online)

For additional information: http://www.karger.com/PHA


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.