Reactive Metabolites: Current and Emerging Risk and Hazard Assessments

Abstract

Although idiosyncratic adverse drug reactions are rare, they are still a major concern to patient safety. Reactive metabolites are widely accepted as playing a pivotal role in the pathogenesis of idiosyncratic adverse drug reactions. While there are today well established strategies for the risk assessment of stable metabolites within the pharmaceutical industry, there is still no consensus on reactive metabolite risk assessment strategies. This is due to the complexity of the mechanisms of these toxicities as well as the difficulty in identifying and quantifying short-lived reactive intermediates such as reactive metabolites. In this review, reactive metabolite risk and hazard assessment approaches are discussed, and their pros and cons highlighted. We also discuss the nature of idiosyncratic adverse drug reactions, using acetaminophen and nefazodone to exemplify the complexity of the underlying mechanisms of reactive metabolite mediated hepatotoxicity. One of the key gaps moving forward is our understanding of and ability to predict the contribution of immune activation in idiosyncratic adverse drug reactions. Sections are included on the clinical phenotypes of immune mediated idiosyncratic adverse drug reactions and on the present understanding of immune activation by reactive metabolites. The advances being made in microphysiological systems have a great potential to transform our ability to risk assess reactive metabolites, and an overview of the key components of these systems is presented. Finally, the potential impact of systems pharmacology approaches in reactive metabolite risk assessments is highlighted.

Revisiting the Metabolism and Bioactivation of Ketoconazole in Human and Mouse Using Liquid Chromatography–Mass Spectrometry-Based Metabolomics

“…The importance of metabolism is more critical when the drug can be biotransformed into biologically active or reactive metabolites. Especially, the formation of reactive metabolites is believed to be the most important underlying mechanism of idiosyncratic adverse drug reactions and is intensively studied to avoid or manage the reactive metabolite formations [24,25,26,27,33,34,35]. …”

“…Bioactivation refers to metabolic activation of xenobiotics into reactive or toxic metabolites, and can result in drug-induced toxicity [14]. Therefore, effort has focused on the assessment of bioactivation of drug candidates to avoid or manage potential risk during drug development [24,25,26,27]. The most widely used method for detection of reactive metabolites is the addition of trapping agents to microsomes.…”

Prediction of clinically relevant drug‐induced liver injury from structure using machine learning

“…Risk factors are bioactivation by metabolic enzymes (Boelsterli & Lee, ; Thompson, Isin, Ogese, Mettetal, & Williams, ), higher lipophilicity (logP ≥3) and dose (daily dose ≥50 mg) (Chalhoub, Sliman, Arumuganathan, & Lewis, ; Chen, Borlak, & Tong, ; Yu et al, ). In addition, DILI has been observed after low‐dose medications (Lammert et al, ) in patients with a predisposition due to genetic polymorphisms or other ADMET particularities that have gone unrecognized until now, resulting in a false labeling of an adverse event as idiosyncratic.…”

Adduct Formation and Context Factors in Drug Hypersensitivity: Insight from Proteomic Studies

“…This metabolite can be detoxified by conjugation to GSH; however, when paracetamol doses are very high, it can accumulate, deplete cellular stores of GSH and form adducts with cysteine residues in proteins [55]. These adducts have been extensively studied, because overdose of this drug is the most frequent cause of acute liver failure in developed countries.…”