TOXI 31 |
| Inhibitors of p38 alpha kinase are currently being developed for anti-inflammatory indications in human. One of the clinical adverse reactions observed with some of these molecules is hepatotoxicity. We have investigated potential mechanisms of hepatic adverse action of a chemical series of p38 inhibitor compounds by studying histological, clinical pathological, and well as genomics data from rodent toxicity studies across several compounds. The anchorage of gene expression data to clinical pathology and histopathology data played a central role in the development of the hypothesis regarding the possible involvement of gastrointestinal endotoxin (lipopolysaccaride) in the observed hepatotoxicity. Gut sterilization studies in the rat, as well as comparison of toxicity profiles when compounds were administered via the oral vs intravenous route in rat and monkey, supported the proposed hypothesis. It is concluded that gastrointestinal toxicity observed with the specific inhibitors of p38 kinase may be related to the observed hepatotoxicity and thus provide a potential target for remediation of the adverse effects of pharmacotherapy. |
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Drug Safety
2:00 PM-5:00 PM, Tuesday, August 21, 2007 BCEC -- 258C, Oral
Division of Chemical Toxicology |