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Ranitidine treatment during a modest inflammatory response precipitates idiosyncrasy-like liver injury in rats.
Luyendyk, James P; Maddox, Jane F; Cosma, Gregory N; Ganey, Patricia E; Cockerell, Gary L; Roth, Robert A.
Afiliação
  • Luyendyk JP; Department of Pharmacology and Toxicology, Institute for Environmental Toxicology, National Food Safety and Toxicology Center, Michigan State University, East Lansing, MI 48824, USA.
J Pharmacol Exp Ther ; 307(1): 9-16, 2003 Oct.
Article em En | MEDLINE | ID: mdl-12893837
ABSTRACT
Drug idiosyncrasy is an adverse event of unknown etiology that occurs in a small fraction of people taking a drug. Some idiosyncratic drug reactions may occur from episodic decreases in the threshold for drug hepatotoxicity. Previous studies in rats have shown that modest underlying inflammation triggered by bacterial lipopolysaccharide (LPS) can decrease the threshold for xenobiotic hepatotoxicity. The histamine-2 (H2)-receptor antagonist ranitidine (RAN) causes idiosyncratic reactions in people, with liver as a usual target. We tested the hypothesis that RAN could be rendered hepatotoxic in animals undergoing a modest inflammatory response. Male rats were treated with a nonhepatotoxic dose of LPS (44 x 10(6) endotoxin units/kg i.v.) or its vehicle and then 2 h later with a nonhepatotoxic dose of RAN (30 mg/kg i.v.) or its vehicle. Liver injury was evident only in animals treated with both RAN and LPS as estimated by increases in serum alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase activities within 6 h after RAN administration. LPS/RAN cotreatment resulted in midzonal liver lesions characterized by acute necrosuppurative hepatitis. Famotidine (FAM) is an H2-antagonist for which the propensity for idiosyncratic reactions is far less than RAN. Rats given LPS and FAM at a dose pharmacologically equipotent to that of RAN did not develop liver injury. In vitro, RAN sensitized hepatocytes to killing by cytotoxic products from activated neutrophils, whereas FAM lacked this ability. The results indicate that a response resembling human RAN idiosyncrasy can be reproduced in animals by RAN exposure during modest inflammation.
Assuntos
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Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ranitidina / Lipopolissacarídeos / Doença Hepática Induzida por Substâncias e Drogas / Inflamação Limite: Animals Idioma: En Ano de publicação: 2003 Tipo de documento: Article
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Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ranitidina / Lipopolissacarídeos / Doença Hepática Induzida por Substâncias e Drogas / Inflamação Limite: Animals Idioma: En Ano de publicação: 2003 Tipo de documento: Article