Underlying Endotoxemia Augments Toxic Responses to Chlorpromazine: Is There a Relationship to Drug Idiosyncrasy?

Abstract

Idiosyncratic reactions occur in a small fraction (typically Ͻ5%) 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 ϫ 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, ␥-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.Drug idiosyncrasy is an untoward biological response to a therapeutic agent occurring in a small percentage of individuals. Idiosyncratic responses appear to occur independently of dose and have an inconsistent temporal relationship to the course of drug administration (Hollister, 1957). Although drug metabolism polymorphisms and drug allergy are widely presumed to underlie idiosyncratic responses, convincing evidence to support these as causes is lacking for the majority of drugs. Reproducing such responses in animals has been met with little success. Inasmuch as drug idiosyncrasy results in human suffering and considerable cost to pharmaceutical companies, animal models that are able to predict such responses in people before a drug is marketed could have great benefit.Among the many drugs that have caused idiosyncratic reactions in people are aliphatic phenothiazines. For example, chlorpromazine (CPZ) (Thorazine, 10-[3-dimethylaminopropyl]-2-chlorphenothiazine) is a tricyclic antidepressant that has been used as a sedative and antiemetic and for the management of psychotic disorders. Two types of adverse reactions result from phenothiazine usage. First, extrapyramidal side effects such as pseudoparkinsonism, dystonic reactions, and akathisia are common, dose-related side effects that likely result from the blockade of dopamine recepto...

Histological effects of pre-exposure prophylactic consumption of sulfa drugs on Liver and Kidney of albino Wister rats (Rattus novergicus).

“…These observations agrees with those of [16] in which animal model indicated such liver toxicity and he concluded that the effect is dose related and reproduceable.…”

“…The method described by [16] was used to determine body weight of experimental rats. Individual rat was monitored for daily gain in body weight using digital electronic balance (Gilbertini, Italy).…”

Animal Models of Human Disease in Drug Safety Assessment

“…Similarly, the extent of liver injury induced by chlorpromazine (CPZ), a psychotropic drug which has been associated with idiosyncratic cholestatic liver injury, is greatly potentiated by concomitant administration of LPS (Buchweitz et al, 2002). Thus, pretreatment of rats with low doses of LPS, followed by injection of a non-toxic dose of CPZ, caused elevations of plasma aminotransferase activities and increases in the number of hepatic neutrophils.…”

Trovafloxacin Potentiation of Lipopolysaccharide-Induced Tumor Necrosis Factor Release from RAW 264.7 Cells Requires Extracellular Signal-Regulated Kinase and c-Jun N-Terminal Kinase

“…Chlorpromazine (CPZ) is a phenothiazine antipsychotic drug associated with IDILI in humans, and coexposure of rats to CPZ and LPS precipitates liver injury (Buchweitz et al, 2002). Exposure of mice or primary murine hepatocytes to CPZ combined with LPS or the Toll-like receptor 2 agonist lipoteichoic acid resulted in hepatocellular injury that was associated with prolonged JNK activation (Gandhi et al, 2010).…”

“…Among several hypotheses put forth to explain IDILI is the inflammatory stress hypothesis, which states that a mild inflammatory episode interacts with a drug, resulting in hepatotoxicity (Shaw et al, 2010). Animal models based on this hypothesis have been developed for several drugs that have caused IDILI in humans, including chlorpromazine, ranitidine, amiodarone, doxorubicin, sulindac, and trovafloxacin (TVX) (Buchweitz et al, 2002;Luyendyk et al, 2003;Shaw et al, 2007;Hassan et al, 2008;Zou et al, 2009;Lu et al, 2012). In each of these models, bacterial lipopolysaccharide (LPS) was used to cause a modest, nontoxic, acute inflammatory episode.…”