Scope and definitions


The expert database delivers:

  • A comprehensive set of structural alerts/features for reactive metabolite (RM) formation that vastly improves the awareness/avoidance process by forecasting test substances that should be deprioritized. Background further discussed in our White Paper.
  • Unprecedented, facile access to the most relevant background information on mechanisms and drugs involved facilitates your judgements.
  • Continuous updates regarding new alerts, drugs, experimental compounds, and new references keep you at the knowledge front-line.

The user of this tool should appreciate the large limitations of the current knowledge in this area. This regards both which reactive species are formed, the precise way of their formation, and what linkage there is of a certain substructure to the observed adverse effects. To add to this, it is quite likely that many drugs have worsened side-effects caused by multiple types of RMs (for more on our considerations, see Supplementary info).

Abbreviations used within SpotRM+

ADR, adverse drug reaction; AE, adverse event; DILI, drug induced liver injury; EMA, European Medicines Agency; FDA, Food and Drug Administration (USA); IDR, idiosyncratic drug reaction; RM, reactive metabolite.

Classification of drugs is based on perceived severity of adverse drug effects

In the SpotRM+ database all alerts are linked to selected examples of the drugs that have the alert. For a rapid visual impression of the hazard associated with a given alert, the drugs are classified as Red, Yellow, Green or Neutral. Definitions of these classes are:
The drug has shown clinical adverse effects that have a proven or highly probable association with bioactivation to RMs or, regarding preclinical compounds, experiments have shown extensive formation of RMs.
A drug used clinically has been withdrawn or bears regulatory warnings.
Examples: sudoxicam, felbamate, amodiaquine, sitaxentan, lamotrigine and halothane.

The drug contains an alert included in SpotRM+, and there have been some reports of adverse effects that have been discussed in terms of RM formation.
Preclinical compounds have displayed RM formation.
Examples: mirtazapine, zolpidem, atorvastatin, tolmetin and phenazone.

Despite having triggered an RM alert, the drug has been used clinically without reported findings of adverse effects that can be associated with RM formation. The explanations for vindication include low typical dosage or a very low degree of metabolism that involves the relevant substructure. The last-mentioned case often depends on metabolism in other parts of the molecule.
Examples: rivaroxaban, cefuroxime, aripiprazole and tolterodine.

In spite of having a RM alert in the structure the clinical information is insufficient to classify the drug into any of the other categories. This might be because the drug has only recently been introduced or is not widely used, and therefore sufficient safety data have not accumulated. For experimental compounds the relevant in vitro experiments might not have been run.
Examples: formoterol, fluorofelbamate and ranolazine.

Bioactivation is required, chemical reactivity per se is excluded

SpotRM+ focuses exclusively on drugs that are bioactivated to form reactive intermediates. There are quite a number of drugs on the market that give rise to toxic effects, including hepatotoxicity, by being chemically reactive per se. Examples range from beta-lactams to cytotoxic anticancer agents, for example busulfan.

Cytotoxic anticancer agents are largely neglected

A large number of anticancer agents require metabolic bioactivation to achieve cytotoxic therapeutic activity, a principle that also entails many well-known and feared side-effects. For the purpose of SpotRM+, which is to help spotting hidden alerts in “normal” drugs, this kind of overt toxicity is of minor interest and therefore the majority of these drugs have been excluded.

Selection of alerts – focus on the less well-known

It is a delicate task to select the really useful substructures (RM alerts), which will be represented by a well-written SMARTS string for matching in target structures. There are many alerts in SpotRM+ that are associated with well-known negative effects in drug structures, for example a nitroarene. We apologize to the experienced drug designer for this, but for the sake of comprehensiveness it is difficult not to include also the most basic knowledge.