Pharmacokinetic basis of the antiplatelet action of prasugrel

• Published in: Fundamental & clinical pharmacology 2012-02, Vol.26 (1), p.39-46
• Main Authors: Schrör, Karsten, Siller-Matula, Jolanta M., Huber, Kurt
• Format: Article
• Language: English
• Subjects: Administration, Oral; antiplatelet drugs; Biological and medical sciences; clopidogrel; CYP P450 isozymes; Cytochrome P-450 Enzyme System - metabolism; Humans; Medical sciences; Pharmacology. Drug treatments; Piperazines - pharmacokinetics; Piperazines - pharmacology; Piperazines - therapeutic use; platelet aggregation; Platelet Aggregation Inhibitors - pharmacokinetics; Platelet Aggregation Inhibitors - pharmacology; Platelet Aggregation Inhibitors - therapeutic use; prasugrel; Prasugrel Hydrochloride; Prodrugs; Purinergic P2Y Receptor Antagonists - pharmacokinetics; Purinergic P2Y Receptor Antagonists - pharmacology; Purinergic P2Y Receptor Antagonists - therapeutic use; response variability; Thiophenes - pharmacokinetics; Thiophenes - pharmacology; Thiophenes - therapeutic use
• ISSN: 0767-3981; 1472-8206
• DOI: 10.1111/j.1472-8206.2011.00986.x

Prasugrel is the most recent development of thienopyridine‐type antiplatelet drugs. Like the earlier‐generation thienopyridines, i.e. ticlopidine and clopidogrel, prasugrel is also an inactive prodrug that requires metabolic processing in vivo to generate the active antiplatelet metabolite. The efficacy of this bioactivation is the key determinant for the pharmacodynamic potency of the compound, i.e. the irreversible blockade of the platelet P2Y12‐ADP receptor. Prasugrel is rapidly absorbed from the gut. After oral administration of standard‐loading doses of 60 mg, maximum plasma levels of the active metabolite are achieved within 1 h, effective, maximum inhibition of platelet aggregation at 1–2 h. Bioconversion of prasugrel into the active metabolite requires two metabolic steps that occur in sequence. The first is the generation of a thiolactone‐intermediate, mainly by carboxyesterases‐2 in the intestine, the second the cytochrome (CYP)‐dependent conversion of the thiolactone into the active metabolite. This second step involves several cytochromes, most notably CYP3A4, CYP2C19, CYP2B6, and CYP2C9. The enzymatic generation of the active metabolite of prasugrel is much more effective than that of clopidogrel where only about 5% of oral clopidogrel is transformed into the active compound by two‐step CYP‐dependent procedures. About 70% of prasugrel metabolites are excreted in the urine and 30% in the feces. The molar potency of the respective active metabolites of prasugrel and clopidogrel is identical. Thus, the more rapid onset, higher potency and lower interindividual variability of antiplatelet effects of prasugrel as compared to clopidogrel in vivo are entirely because of its more efficient pharmacokinetics.