Structural Alerts, Reactive Metabolites, and Protein Covalent Binding: How Reliable Are These Attributes as Predictors of Drug Toxicity?

Abstract

In an increasing number of cases, a deeper understanding of the biochemical basis for idiosyncratic adverse drug reactions (IADRs) has aided to replace a vague perception of a chemical class effect with a sharper picture of individual molecular peculiarity. Considering that IADRs are too complex to duplicate in a test tube, and their idiosyncratic nature precludes prospective clinical studies, it is currently impossible to predict which new drugs will be associated with a significant incidence of toxicity. Because it is now widely appreciated that reactive metabolites, as opposed to the parent molecules from which they are derived, are responsible for the pathogenesis of some IADRs, the propensity of drug candidates to form reactive metabolites is generally considered a liability. Procedures have been implemented to monitor reactive-metabolite formation in discovery with the ultimate goal of eliminating or minimizing the liability via rational structural modification of the problematic chemical series. While such mechanistic studies have provided retrospective insight into the metabolic pathways which lead to reactive metabolite formation with toxic compounds, their ability to accurately predict the IADR potential of new drug candidates has been challenged. There are several instances of drugs that form reactive metabolites, but only a fraction thereof cause toxicity. This review article will outline current approaches to evaluate bioactivation potential of new compounds with particular emphasis on the advantages and limitation of these assays. Plausible reason(s) for the excellent safety record of certain drugs susceptible to bioactivation will also be explored and should provide valuable guidance in the use of reactive-metabolite assessments when nominating drug candidates for development.

Disposition and Metabolism of [14C]SB-649868, an Orexin 1 and 2 Receptor Antagonist, in Humans

“…The formation of reactive metabolites has been linked to certain toxicities, e.g., hepatotoxicity, which may involve modification of proteins and/or direct cell damage, either of which could induce an immune-mediated response, although proper elucidation of this relationship remains unclear (Uetrecht, 2008). Furthermore, the proposed low therapeutic dose of SB-649868 (20 mg) reduces the risk of toxicity associated with the presence of a reactive pathway, because the daily dose seems to be a key underlying factor in drug toxicity (Lammert et al, 2008;Kalgutkar and Didiuk, 2009).…”

Cytochrome P450 Architecture and Cysteine Nucleophile Placement Impact Raloxifene-Mediated Mechanism-Based Inactivation

“…A key differentiating factor for a xenobiotic to form a benign, oxidative metabolite or a reactive metabolite is the innate chemistry of the xenobiotic (Nelson, 1982). The term structural alert classifies a set of chemical functional groups prone to P450-mediated reactive metabolite formation (Kalgutkar and Didiuk, 2009;Stepan et al, 2011). Exposure of these functional groups to P450 enzymes is anticipated to increase the probability of reactive metabolite formation; therefore, strategies to identify and limit reactive metabolite formation are of importance.…”

Novel Metabolic Bioactivation Mechanism for a Series of Anti-Inflammatory Agents (2,5-Diaminothiophene Derivatives) Mediated by Cytochrome P450 Enzymes

“…Upon the removal of a proton (oxidation) from one of the nitrogens adjacent to the sulfur atom (C2 or C5) an extended series of conjugated double bonds is formed, which is subject to nucleophilic attack at the C3 atom. This reactive intermediate is a 2,5-diimine metabolite and is analogous to several well known reactive 1,4-quinoid species (e.g., quinones, quinone methides, and quinone imines) formed from the oxidation of phenyl rings with the appropriate substituents attached (Monks and Jones, 2002;Kalgutkar and Didiuk, 2009). Thus, we propose a novel metabolic activation mechanism, "2,5-diimine thiophene reactive intermediate," for 2,5-diaminothiophene derivatives, distinct from the previously described sulfur oxidation and epoxidation pathways (Fig.…”