Establishment of drug hypersensitivity animal model and investigation of the mechanism.

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Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are major causes to attrition during clinical studies. Formation of reactive metabolites of drugs by drug-metabolizing enzymes has been focused. Considering the species differences and interindividual differences, studies for developing the prediction method of SJS/TEN in non-clinical drug development were conducted. However, SJS/TEN with very low incidence are hard to predict, because the immune- and inflammatory-related factors were not able be considered. Recently, we have established animal models of drug-induced liver injury in 10 kinds of clinical drugs. However, the phenotypic consequence of SJS/TEN in mouse model showed very low reproducibility, even with many difference experimental conditions. Thus, we clarified the mechanism of hepatic inflammation by carbamazepine and phenytoin (representative drugs for SJS/TEN) in mouse.