Inflammation and Drug Idiosyncrasy—Is There a Connection?

Abstract

"Drug idiosyncrasy" refers to untoward reactions to drugs that occur in a small fraction of patients and have no obvious relationship to dose or duration of therapy. The liver is a frequent target for toxicity. Much of the conventional thinking about mechanisms of drug idiosyncrasy has centered on hypotheses that the reactions have a metabolic basis involving drug metabolism polymorphisms or that they arise from a specific immune response to the drug or its metabolite(s). For very few drugs does convincing evidence exist for either of these mechanisms, however. The erratic temporal and dose relationships that characterize idiosyncratic drug responses suggest the possibility that some event during the course of therapy renders tissues peculiarly susceptible to toxic effects of the drug. For example, episodes of inflammation are commonplace in people, and results of numerous studies in animals indicate that a modest inflammatory response can enhance tissue sensitivity to a variety of toxic chemicals. These observations have led to the hypothesis that an episode of inflammation during drug therapy could decrease the threshold for drug toxicity and thereby render an individual susceptible to a toxic reaction that would not otherwise occur (i.e., an "idiosyncratic" response). This hypothesis can explain the features of drug idiosyncrasy using fundamental pharmacologic principles, and results of recent animal studies are supportive of this. Knowledge gaps that need to be filled before the hypothesis should be widely accepted are discussed.

Concurrent Inflammation Augments Antimalarial Drugs-Induced Liver Injury in Rats

“…56 On the other hand, inflammatory stress might sensitize the liver to xenobiotics-induced injury. 57 Hence, we might be able to suggest that inflammatory stress occurring during antimalarial drug therapy might participate in antimalarial drugs-induced liver injury in patients and enhance the sensitivity to antimalarial drugs. Investigating the effect of inflammation on antimalarial drugs hepatotoxicity in a broader time frame will enhance our understanding of the mechanism of toxicity and the pathological pattern of liver injury induced by…”

Idiosyncratic Drug Reactions: Past, Present, and Future

“…Roth found that cotreatment of animals with lipopolysaccaride (LPS) and drugs such as ranitidine causes immediate hepatic damage (42). He has proposed that we are commonly exposed to inflammagens such as LPS, and it is the combination of drug and inflammagen that leads to hepatic damage.…”

NSAID-Induced Acute Phase Response is Due to Increased Intestinal Permeability and Characterized by Early and Consistent Alterations in Hepatic Gene Expression

“…Despite the lesser attention to the gut, an estimated 16,500 or more people die annually in the U.S. from complications associated with long term NSAID use (e.g., intestinal ulceration, bleeding, perforations, and strictures (Hirschowitz, 1994;Laney et al, 1994)), especially among elderly, arthritic patients (Wolfe et al, 1999). Moreover, an appreciated aspect of persistent low-level LPS exposure due to NSAID use is elevated risk of drug-induced idiosyncratic hepatic injuries (Roth et al, 2003), atherosclerosis (Blake and Ridker 2001;Shishehbor and Bhatt, 2004) and alcohol-induced hepatic injury (Mathurin et al, 2000;Schafer et al, 2002). To this point, pretreatment of rats with a mild APR inducing dose of LPS followed by a dose of ranitidine that in naïve animals is only mildly hepatotoxic synergistically increases hepatic injury (Luyendyk et al, 2003).…”