title: Underlying endotoxemia augments toxic responses to chlorpromazine: is there a relationship to drug idiosyncrasy?
abstract: Idiosyncratic reactions occur in a small fraction (typically <5%) of the population taking therapeutic drugs. Chlorpromazine (CPZ) is a phenothiazine, antipsychotic drug that has caused several idiosyncratic responses during its therapeutic use. Clinical evidence suggests that conditions associated with inflammation are risk factors for the appearance of these responses. Accordingly, we tested the hypothesis that an inflammatory stimulus, bacterial lipopolysaccharide (LPS), renders animals susceptible to CPZ-induced idiosyncratic reactions seen in humans. Male Sprague-Dawley rats (200-250 g) were fasted for 24 h. A small dose of LPS (7.4 x 10(6) EU/kg from Escherichia coli) or its vehicle (saline) was administered by tail vein 2 h before an intraperitoneal injection of CPZ (70 mg/kg) or its vehicle (saline). Cholestasis and hepatocellular necrosis were evaluated as increased concentrations of serum bile acids and bilirubin and increased activities of alkaline phosphatase, gamma-glutamyltransferase, alanine aminotransferase, and aspartate aminotransferase. With the exception of bile acids, these serum markers were elevated in animals treated with LPS/CPZ. Histopathological lesions in liver sections were consistent with these findings. Elevated serum creatine kinase activity, which is associated with human idiosyncratic responses to phenothiazines, was also found in animals treated with LPS/CPZ, but not with either LPS or CPZ alone. These results raise the possibility that concurrent, modest inflammation may underlie susceptibility of individuals to certain idiosyncratic reactions and may form the basis for an animal model with which to understand and predict drug idiosyncrasy.
authors.affiliation: Department of Pharmacology, Michigan State University, East Lansing, Michigan 48824, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Buchweitz
authors.forename: Patricia E
authors.initials: PE
authors.lastname: Ganey
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Bursian
authors.forename: Robert A
authors.initials: RA
authors.lastname: Roth
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002746:Chlorpromazine / Q000633:toxicity*; D002779:Cholestasis / Q000201:enzymology / Q000378:metabolism; D003402:Creatine Kinase / Q000097:blood / Q000378:metabolism; D004731:Endotoxins / Q000097:blood* / Q000633:toxicity*; D007249:Inflammation / Q000097:blood / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000097:blood / Q000633:toxicity*; D008297:Male; D009336:Necrosis; D009504:Neutrophils / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D014150:Antipsychotic Agents; D004731:Endotoxins; D008070:Lipopolysaccharides; C044101:endotoxin, Escherichia coli; D003402:Creatine Kinase; D002746:Chlorpromazine