Systematic Approach to Organizing Structural Alerts for Reactive Metabolite Formation from Potential Drugs

Abstract

Reactive metabolites are widely accepted as playing a pivotal role in causing idiosyncratic adverse drug reactions (IDR). However, much is unknown about the biological mechanisms of IDR, although the initiating event in most cases is an attachment of a reactive intermediate to macromolecules leading to immune-mediated responses. Reactive metabolites are also involved in many mutagenesis/carcinogenesis events by reacting with DNA. Drug designers thus have reasons to make large efforts to avoid making test compounds having a liability to generate reactive metabolites. In this Perspective we argue for using structural alerts (SA) as the most straightforward way to link forecasting about chemical hazards of planned test compounds to the accumulated knowledge base. Although many SAs have been widely recognized and reviewed previously, there are also a lot of observations that have no readily discernible chemical interpretation. For drug designers to benefit from all published data, the knowledge has to be organized in a way that is readily searchable starting with a query structure. We propose that an increased number of structural alerts with more details should be applied to obtain improved decision support. The association of selected SAs with reference drugs, whose proposed or hypothesized activation mechanisms build the knowledge base, should be readily available in a format comprising of small summaries with included hyperlinks for quick access to the original literature, as outlined in the TOC illustration. Since some structural alerts are present in drugs that do not cause idiosyncratic adverse reactions or drug-drug interactions, it is important to elaborate on the reasons for this discrepancy as much as possible.

Identifying the reactive metabolites of tyrosine kinase inhibitors in a comprehensive approach: Implications for drug‐drug interactions and hepatotoxicity

“…Similarly, a carboxylic acid metabolite 80 was identified in humans for famitinib 17 in urine and feces (Figure ). Finally, bioactivation of the alcohol derivative 81 to a methide RM, mentioned by Claesson et al, has not been observed, but GSH has not been used in this study …”

“…71,73 Similarly, a carboxylic acid metabolite 80 was identified in humans for famitinib 17 in urine and feces 40 ( Figure 20). Finally, bioactivation of the alcohol derivative 81 to a methide RM, mentioned by Claesson et al, 21 has not been observed, but GSH has not been used in this study. 72 F I G U R E 2 0 Proposed mechanism of sunitinib metabolic activation to an aldehyde intermediate; famitinib and sunitinib biotransformations to carboxylic acids are also presented PALUDETTO ET AL.…”

“…To conclude, the state of the art current knowledge of RM generation from TKI showed that the understanding related to structural alerts and RM formation mechanisms still needs to be improved as recently pointed out by Claesson et al in advancing new hypotheses of the mechanisms underlying CYP inactivation and hepatoxicity. New tools are also needed to better predict RM‐mediated TKI‐induced hepatotoxicity and DDI in humans.…”

“…The formation of 98a and 98b was reported in HLM and in mice urine and feces, with a possible oxidation of 98b into carboxylic acid . The formation of a p ‐imine‐methide upon oxidation of the p ‐methylaniline structural alert, mentioned several times, is supported by the detection of a GSH adduct and of cysteine, N ‐acetylcysteine, and glycylcysteine adducts in mice and human, although this mechanism was nor clearly reported nor discussed (Figure ).…”

“…86 Pharmacokinetic modeling incorporating in vitro generated parameters might be useful and is increasingly applied in this field. 85,155 To conclude, the state of the art current knowledge of RM generation from TKI showed that the understanding related to structural alerts and RM formation mechanisms still needs to be improved as recently pointed out by Claesson et al 21 in advancing new hypotheses of the mechanisms underlying CYP inactivation and hepatoxicity.…”