Ranitidine Treatment during a Modest Inflammatory Response Precipitates Idiosyncrasy-Like Liver Injury in Rats

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 ϫ 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 ␥-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.Adverse drug reactions of unknown etiology that occur in a small fraction of the treated population are defined as idiosyncratic. These reactions are typically unpredictable, show no obvious relation to dose, and display a variable time to onset in relation to start of drug therapy.

Role of hepatic fibrin in idiosyncrasy-like liver injury from lipopolysaccharide-ranitidine coexposure in rats

“…Rats were treated with LPS and/or RAN, and immunostaining for PIM-adducts and HIF-1␣ protein was evaluated at a time near the onset of hepatotoxicity in LPS/RAN-treated rats (i.e., 3 hours after RAN administration). In contrast to previous experiments, 5 serum ALT activity was significantly increased at 3 hours in LPS/RAN-treated rats compared with rats given only LPS or RAN (data not shown), suggesting that 3 hours marks the approximate time of onset of liver injury in this model. LPS/RAN hepatotoxicity was not influenced by PIM administration (data not shown).…”

“…Prodromal signs consistent with inflammation/endotoxemia often accompany idiosyncratic liver injury from RAN in people. 5 Treatment with a small, nonhepatotoxic dose of LPS renders rats susceptible to liver toxicity from an otherwise nonhepatotoxic dose of RAN, suggesting a role for inflammation in precipitating idiosyncratic reactions to this drug. 5 Exposure of rats to large doses of LPS results in midzonal hepatic necrosis that requires several factors, including cytokines, inflammatory cells, an activated coagulation system, and platelets.…”

“…5 Treatment with a small, nonhepatotoxic dose of LPS renders rats susceptible to liver toxicity from an otherwise nonhepatotoxic dose of RAN, suggesting a role for inflammation in precipitating idiosyncratic reactions to this drug. 5 Exposure of rats to large doses of LPS results in midzonal hepatic necrosis that requires several factors, including cytokines, inflammatory cells, an activated coagulation system, and platelets. 6 -9 The involvement of similar factors in LPS/RAN-induced hepatotoxicity has not been investigated, but recent results suggested the possibility that the hemostatic system is important in this model.…”

“…Prodromal signs consistent with inflammation/endotoxemia often accompany idiosyncratic liver injury from RAN in people. 5 Treatment with a small, nonhepatotoxic dose of LPS renders rats susceptible to liver toxicity from …”

Idiosyncratiques et « omiques » peuvent-ils rimer ?

“…Ainsi, un épisode inflammatoire suffisamment intense chez un patient pourrait abaisser le seuil de toxicité de certains médicaments [28]. La réponse inflammatoire, qui constitue l'élément essentiel de la dynamique de l'immunité innée, serait en étroite connexion avec la réponse immunitaire (immunité acquise) et jouerait un rôle potentialisateur majeur dans les premières étapes de la réponse immunitaire.…”