[Prasugrel, a new thienopyridine].
The introduction of thienopyridines, specifically of clopidogrel, offered for the first time an orally active therapeutic alternative to acetylsalicylic acid (ASA) as an antiplatelet agent. Despite of established clinical efficacy, it became also evident with increasing clinical use that the antiplatelet actions of clopidogrel are subject of considerable interindividual variations of its antiplatelet efficacy (clopidogrel resistance) in laboratory tests which might also be clinically relevant. Prasugrel is a new, orally active thienopyridine with an expected spectrum of biological activities similar to clopidogrel. Prasugrel, like clopidogrel, is also an inactive prodrug that has to be transformed into the active metabolite by the liver cytochrome P450 system. However, different cytochromes appear to be involved for different extent in the generation of the active metabolite. The active metabolite of prasugrel, R-138727, inhibits irreversibly the platelet P2Y(12) ADP receptor. In contrast to ASA, neither clopidogrel nor prasugrel inhibit the arachidonic acid metabolism. This allows synergistic interactions with ASA as thromboxane inhibitor and PGI(2) as stimulator of cAMP-formation in platelets. Prasugrel is orally more potent and acts more rapidly than clopidogrel, allowing lower oral dosing despite of similar in vitro activity of the active metabolites. These pharmacological advantages of prasugrel are probably due to its improved pharmacokinetics, i.e. the higher conversion rate of the prodrug into the active metabolite. In case of clopidogrel, only about 10-15% of the prodrug is converted into the active metabolite. This higher conversion rate possibly also explains the more rapid onset of platelet inhibition, the lower interindividual variability and higher oral potency with apparently less "resistance" than clopidogrel. Clinically, this might result in an improved efficacy. Whether this is associated with an increased risk of bleeding will be seen from the first phase III clinical trial in PCI-patients. The first results are expected at the end of the year.
Institutes für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum Düsseldorf, Universitätsstrasse 1, Geb. 22.21, 40225 Düsseldorf. karsten.schroer@uni-duesseldorf.de
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D017322:Clinical Trials, Phase II as Topic; D000077144:Clopidogrel; D003328:Coronary Thrombosis / Q000188:drug therapy; D006801:Humans; D010879:Piperazines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000068799:Prasugrel Hydrochloride; D058919:Purinergic P2 Receptor Antagonists; D013876:Thiophenes / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use
D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D013876:Thiophenes; D000077144:Clopidogrel; D000068799:Prasugrel Hydrochloride; D013988:Ticlopidine