title: Oral administration of drugs with hypersensitivity potential induces germinal center hyperplasia in secondary lymphoid organ/tissue in Brown Norway rats, and this histological lesion is a promising candidate as a predictive biomarker for drug hypersensitivity occurrence in humans.
abstract: It is important to evaluate the potential of drug hypersensitivity as well as other adverse effects during the preclinical stage of the drug development process, but validated methods are not available yet. In the present study we examined whether it would be possible to develop a new predictive model of drug hypersensitivity using Brown Norway (BN) rats. As representative drugs with hypersensitivity potential in humans, phenytoin (PHT), carbamazepine (CBZ), amoxicillin (AMX), and sulfamethoxazole (SMX) were orally administered to BN rats for 28days to investigate their effects on these animals by examinations including observation of clinical signs, hematology, determination of serum IgE levels, histology, and flow cytometric analysis. Skin rashes were not observed in any animals treated with these drugs. Increases in the number of circulating inflammatory cells and serum IgE level did not necessarily occur in the animals treated with these drugs. However, histological examination revealed that germinal center hyperplasia was commonly induced in secondary lymphoid organs/tissues in the animals treated with these drugs. In cytometric analysis, changes in proportions of lymphocyte subsets were noted in the spleen of the animals treated with PHT or CBZ during the early period of administration. The results indicated that the potential of drug hypersensitivity was identified in BN rat by performing histological examination of secondary lymphoid organs/tissues. Data obtained herein suggested that drugs with hypersensitivity potential in humans gained immune reactivity in BN rat, and the germinal center hyperplasia induced by administration of these drugs may serve as a predictive biomarker for drug hypersensitivity occurrence.
authors: Safety Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., 3-1-98, Kasugade Naka, Konohanaku, Osaka, 554-0022, Japan. akitoshi-tamura@ds-pharma.co.jp
authors: Akitoshi
authors: A
authors: Tamura
authors: Izuru
authors: I
authors: Miyawaki
authors: Toru
authors: T
authors: Yamada
authors: Juki
authors: J
authors: Kimura
authors: Hitoshi
authors: H
authors: Funabashi
mesh_terms: D000284:Administration, Oral; D000658:Amoxicillin / Q000008:administration & dosage / Q000633:toxicity; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002220:Carbamazepine / Q000008:administration & dosage / Q000633:toxicity; D004342:Drug Hypersensitivity / Q000209:etiology*; D005434:Flow Cytometry; D018858:Germinal Center / Q000187:drug effects* / Q000473:pathology; D006965:Hyperplasia; D007073:Immunoglobulin E / Q000097:blood*; D008221:Lymphoid Tissue / Q000187:drug effects* / Q000473:pathology; D010672:Phenytoin / Q000008:administration & dosage / Q000633:toxicity; D051381:Rats; D011914:Rats, Inbred BN; D013420:Sulfamethoxazole / Q000008:administration & dosage / Q000633:toxicity
chemical_list: D015415:Biomarkers; D002220:Carbamazepine; D007073:Immunoglobulin E; D010672:Phenytoin; D000658:Amoxicillin; D013420:Sulfamethoxazole
keywords: Brown Norway rat; Drug hypersensitivity; Germinal center hyperplasia; Predictive biomarker