Are drugs containing a carboxylic acid functional group associated with a significant risk of idiosyncratic drug reactions?
DOI:
https://doi.org/10.12970/2308-8044.2020.08.07Keywords:
Acyl glucuronides, Co-A esters, Idiosyncratic drug reactions, Immune mediated, Reactive metabolites, Adverse drug reactions.Abstract
Most drugs that contain a carboxylic acid are metabolized to acyl glucuronides. Although the reactivity of these metabolites varies, acyl glucuronides can clearly react with proteins. There is circumstantial evidence that many idiosyncratic drug reactions are caused by reactive metabolites; therefore, it is quite plausible that the reactive metabolites of carboxylic acids would cause such reactions. However, not all drugs that form reactive metabolites are associated with a significant risk of idiosyncratic reactions. In fact, the carboxylic acid functional group is common, and in most cases the drugs are quite safe. The largest problem is with nonsteroidal antiinflammatory drugs, and much of the associated adverse reactions are related to their pharmacological action. In most other cases there is an alternative reactive metabolite. This raises the question as to why the reactive acyl glucuronides are not associated with a higher risk of idiosyncratic reactions. It appears that for a drug to provoke an immune response it must do two things: form a neoantigen and cause cell damage. It is possible that the amide bond formed when acyl glucuronides react with proteins is cleaved when antigens are processed, which also involves cleavage of amide bonds. Given that acyl glucuronides are less reactive than most reactive metabolites formed by oxidation, they may also not cause significant cell damage. It is possible that some idiosyncratic reactions are caused by reactive metabolites of carboxylic acids; however, overall the carboxylic acid functional group is very important and is generally not associated with a significant risk.References
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