""""""""Drug idiosyncrasy"""""""" refers to a toxic response to a drug that occurs in a small fraction of people and bears no obvious relationship to dosing regimen. Numerous drugs developed for various therapeutic purposes have produced in people idiosyncratic responses that have resulted in serious injury to liver and other organs. These reactions typically do not become apparent in preclinical animal studies, and little is understood about underlying mechanisms. Animal models with the potential to enable prediction/early identification of idiosyncratic responses could prevent human suffering and lead to understanding of mechanisms. In preliminary studies, we have found in rats that modest inflammation produced by a small, nontoxic dose of endotoxin (LPS) can render an otherwise nonhepatotoxic drug hepatotoxic. For example, in rats given a nontoxic dose of chlorpromazine, co treatment with a small dose of LPS resulted in liver injury and elevated plasma creatine kinase activity, two responses that occur idiosyncratically in people during therapy with this and related drugs. Similarly, a nontoxic dose of LPS; can render ranitidine hepatotoxic in rats and mice. These preliminary results suggest a novel mechanism for drug idiosyncrasy and raise the possibility of creating useful animal models for such responses in humans. The hypothesis to be tested is that idiosyncratic drug reactions that occur in humans can be reproduced in animals by drug administration during a concurrent episode of mild inflammation. Several drugs that have caused idiosyncratic liver injury in humans (chlorpromazine, ranitidine, flutamide) and two that have not (promethazine, famotidine) will be used. Rats will be co exposed to a drug and to a dose of LPS that causes """"""""modest inflammatory response"""""""" to determine if the co treatment reproduces the idiosyncratic drug responses that people experience. Dose-response and temporal relationships will be defined. Inflammatory factors (e.g. neutrophils, tumor necrosis factor-alpha, cyclooxygenase 2) likely to be critical to the toxic response will be evaluated. In addition, a cell-based, in vitro system will be developed and used to explore intracellular signaling mechanisms that enable drugs to interact with inflammatory factors to result in synergistic hepatocyte killing. Results from these studies will be an important step toward creating predictive animal models of human drugs idiosyncrasy and exploring underlying mechanisms. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK061315-03
Application #
6936690
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Serrano, Jose
Project Start
2003-09-01
Project End
2007-07-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
3
Fiscal Year
2005
Total Cost
$231,726
Indirect Cost
Name
Michigan State University
Department
Pharmacology
Type
Schools of Veterinary Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
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