title: A new mechanism of action of thienopyridine antiplatelet drugs - a role for gastric nitrosthiol metabolism?
abstract: 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)) +  [Formula: see text] ↔ 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.
authors.affiliation: Department of Cardiology, University Hospital of Wales, UK. Electronic address: RAAnderson15@outlook.com.
authors.forename: R A
authors.initials: RA
authors.lastname: Anderson
authors.affiliation: Department of Cardiology, University Hospital of Wales, UK.
authors.forename: S
authors.initials: S
authors.lastname: Bundhoo
authors.affiliation: Wales Heart Research Institute, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: P E
authors.initials: PE
authors.lastname: James
mesh_terms: D054058:Acute Coronary Syndrome / Q000188:drug therapy; D001792:Blood Platelets / Q000187:drug effects; D000077144:Clopidogrel; D005753:Gastric Mucosa / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008954:Models, Biological; D009566:Nitrates / Q000737:chemistry; D009569:Nitric Oxide / Q000737:chemistry; D009584:Nitrogen / Q000378:metabolism*; D010100:Oxygen / Q000737:chemistry; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry*; D058925:Receptors, Purinergic P2Y12 / Q000378:metabolism; D026403:S-Nitrosothiols / Q000378:metabolism*; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000737:chemistry
chemical_list: D009566:Nitrates; C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D058925:Receptors, Purinergic P2Y12; D026403:S-Nitrosothiols; D013438:Sulfhydryl Compounds; C446540:thienopyridine; D009569:Nitric Oxide; D000077144:Clopidogrel; D009584:Nitrogen; D013988:Ticlopidine; D010100:Oxygen
keywords: Clopidogrel; Nitrosothiols; Platelet inhibition; Platelets