A new mechanism of action of thienopyridine antiplatelet drugs - A role for gastric nitrosothiol metabolism
Author
Anderson, R. A.
Bundhoo, S.
James, Philip
Date
2014-09-09Acceptance date
2014-08-29
Type
Article
Publisher
Elsevier
ISSN
0021-9150
Metadata
Show full item recordAbstract
This article outlines a new hypothesis that illustrates the potential role of the stomach (and subsequent chemical reactions involving nitrite therein) in modifying thienopyridines, such as clopidogrel. Gastric modification of thienopyridines can occur before standard accepted biotransformation pathways ensue. We hypothesised that thienopyridines expose the free thiol group once acidified (by the stomach) before biotransformation into active metabolites, and in the presence of nitrite (from saliva and the stomach) to form nitrosothiol derivatives (Thienopyridine induced-SNO formation). We have performed in vitro studies with each of the thienopyridines tablets/compounds confirming direct Th-SNO formation from the parent (inactive) drug by the following mechanism. Thienopyridine-SH + H+ (Stomach) + View the MathML sourceNO2−(Salivaandstomach) ↔ Thienopyridine-SNO + H2O
Thienopyridine-SNO (an S-nitrosothiol molecule) would have the potential to participate in all the reactions expected of native nitric oxide (NO) with added benefit that the NO “moiety” is protected, transportable and largely preserved from further reactive metabolism. All these biochemical steps are present in humans and could occur prior to enzymatic biotransformation.
Journal/conference proceeding
Atherosclerosis;
Citation
Anderson, R.A., Bundhoo, S. and James, P.E. (2014) 'A new mechanism of action of thienopyridine antiplatelet drugs–A role for gastric nitrosthiol metabolism?', Atherosclerosis, 237(1), pp.369-373
Description
This article was published in Atherosclerosis on 9 September 2014 (online), available at http://dx.doi.org/10.1016/j.atherosclerosis.2014.08.045
Sponsorship
Cardiff Metropolitan University (Grant ID: Cardiff Metropolian (Internal))