Role of Metabolism in Drug-Induced Idiosyncratic Hepatotoxicity

Abstract

Rare adverse reactions to drugs that are of unknown etiology, or idiosyncratic reactions, can produce severe medical complications or even death in patients. Current hypotheses suggest that metabolic activation of a drug to a reactive intermediate is a necessary, yet insufficient, step in the generation of an idiosyncratic reaction. We review evidence for this hypothesis with drugs that are associated with hepatotoxicity, one of the most common types of idiosyncratic reactions in humans. We identified 21 drugs that have either been withdrawn from the U.S. market due to hepatotoxicity or have a black box warning for hepatotoxicity. Evidence for the formation of reactive metabolites was found for 5 out of 6 drugs that were withdrawn, and 8 out of 15 drugs that have black box warnings. For the other drugs, either evidence was not available or suitable studies have not been carried out. We also review evidence for reactive intermediate formation from a number of additional drugs that have been associated with idiosyncratic hepatotoxicity but do not have black box warnings. Finally, we consider the potential role that high dosages may play in these adverse reactions.

Mitochondrial superoxide dismutase and glutathione peroxidase in idiosyncratic drug-induced liver injury

“…Many drugs undergo bioactivation in the liver that may or may not lead to the formation of reactive intermediates or metabolites, such as quinones, epoxides, and diazenes, that could potentially cause cellular damage. 11,12 Focusing on the chemical structure of reactive metabolites/intermediates formed rather than the parent drug may thus provide better insight into the underlying mechanism and equivalent determinants of DILI development. Both of the two groups of reactive intermediates focused on in this study displayed a significant association between the SOD2 Ala/Ala genotype and the risk of developing cholestatic/mixed type of liver injury.…”

“…10 The aforementioned drugs were also classified according to their ability to form reactive intermediates (quinones, quinone methides, quinone imines, epoxides, S-oxides, diazenes, nitroanion radicals, and iminium ions) and known mitochondrial hazards based on thorough searches of published information. [11][12][13][14] Patients who gave informed consent and for whom a blood sample was available were considered eligible only if the causality assessment score was ''definite'' or ''probable.'' Excluded were cases secondary to drug overdoses (acetaminophen) and occupational exposure to toxins.…”

Safety and Tolerability of Antiepileptic Drug Treatment in Children with Epilepsy

“…[83] Since the formation of 4-en-VPA is largely catalyzed by CYP2C9, whose activity is inducible and higher in infants co-medicated with enzyme-inducing AEDs, this finding may explain why the risk of VPA-induced liver toxicity is highest in infants who are co-medicated with enzyme-inducing AEDs. [84] Immune-mediated hypersensitivity reactions: These reactions involve abnormal humoral-or cell-mediated responses. AEDs may initiate these responses by interacting with cells of adaptive immunity.…”

“…[89] Children are at higher risk of LTG-induced idiosyncratic reactions because their CYP enzymatic system is faster and glucuronide conjugation slower compared with adults. [83][84][85][86][87][88][89][90] Considerable evidence indicates that FBM-induced liver and bone marrow toxicity is mediated by the reactive metabolite atropaldehyde. [91,92] Both atropaldehyde and another FBM metabolite, alcohol carbamate, have been shown to inhibit glutathione transferase and cause cytotoxicity in human hepatocytes.…”

A malleable catalyst dominates the metabolism of drugs

“…Ketoconazole has a ''black-box'' warning for its use as a drug, i.e., a patient takes this at his or her own risk (20).…”