TOXI 34 |
| A modest inflammatory stress occurring during drug therapy can enhance the sensitivity of an individual to drug hepatotoxicity, and this might be the basis for some idiosyncratic adverse drug reactions (IADRs) in people. In animals, drug-inflammation interaction resulting in liver injury has now been demonstrated for several drugs that cause human IADRs. For example, exposure of rats or mice to a small dose of bacterial lipopolysaccharide (LPS) that causes an otherwise innocuous inflammatory reaction results in liver injury upon coexposure to trovafloxacin (TVX). In contrast, treatment of rats with LPS and levofloxacin, a drug in the same pharmacologic class as TVX but without idiosyncrasy liability, failed to cause liver injury. Factors that appear to be involved in hepatotoxic drug-LPS interactions include inflammatory cytokines, neutrophils and an activated hemostatic system. Exploring drug interaction with inflammatory stress in animals could enhance understanding of human IADRs and provide the basis for developing animal and/or in vitro models for preclinical prediction of idiosyncratic potential of drug candidates. |
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Drug Safety
2:00 PM-5:00 PM, Tuesday, August 21, 2007 BCEC -- 258C, Oral
Division of Chemical Toxicology |