Plavix is a potent antiaggregant and antithrombotic drug, as demonstrated in several experimental models of thrombosis. The drug was launched on the market following a successful clinical evaluation and demonstration of superior efficacy versus aspirin in preventing thrombotic events (myocardial infarction, stroke, and vascular death) in high risk patients.
Plavix inhibits platelet aggregation ex vivo induced by ADP, low concentrations of thrombin, or by collagen. The specific pharmacological target of plavix is the ADP-induced platelet activation process, and it has been described as a specific and irreversible inhibitor of binding to its platelet receptors, the purinergic P2Y12 receptor .
Plavix is not active in vitro, and a biotransformation by the liver is necessary to allow the expression of its antiaggregating activity. Therefore, Plavix can be considered as a precursor of an active metabolite. Moreover, no antiaggregating activity was found in platelet poor plasma of SR25990C-treated animals or humans, indicating a high reactivity and
instability of the active metabolite.
Plavix has an absolute S configuration at carbon 7. The corresponding R enantiomer is totally devoid of antiaggregating activity, thus indicating the importance of the configuration of this asymmetric carbon for the biological
activity. In previous experiments. Similar results were obtained using human liver microsomes. Despite being not active in vitro, 2-oxo-Plavix can demonstrate an antiaggregating activity ex vivo, thus indicating that the formation of the active metabolite of plavix occurred downstream to the formation of 2-oxo-Plavix. The structure of active metabolite of another thienopyridine, was reported. In another report, these authors indicated the precise absolute configuration to express the biological activity, since only one among the four optical isomers showed activity in inhibiting platelet aggregation.
However, to our knowledge, no structural and stereochemical characterization data were published in detail concerning this active metabolite. The objective of this work was to identify the chemical structure of the active metabolite of plavix. For this purpose, metabolites generated after incubation of human liver microsomes with 2-oxoclopidogrel and its corresponding inactive R enantiomer were isolated and purified using a two-step liquid chromatographic procedure. The biological activity of the metabolites was evaluated through the inhibition of binding of radiolabeled 2-methyl-S-ADP to rat platelets.
Subsequently, the structure and stereochemistry of the metabolites
were studied by a combination of mass spectrometry and chiral supercritical fluid chromatography.
Clinical Results of Plavix
The clearance to market PLAVIX was based primarily on the results of the CAPRIE clinical trial, a randomized, double-blind trial that enrolled 19,185 patients who had suffered a recent ischemic stroke, recent heart attack, or had established peripheral arterial disease.
CAPRIE compared the efficacy and safety of Plavix and aspirin in reducing subsequent strokes, heart attacks, and other vascular events in patients treated for a period of one to three years.
Side Effects of Plavix
PLAVIX is contraindicated in patients with active pathologic bleeding or who have shown hypersensitivity to the drug or any component of the drug and should be used with caution in patients with severe liver disease. The most frequent side effects are rash, diarrhea, and pruritis.
