Metabolism and Disposition of the Thienopyridine Antiplatelet Drugs Ticlopidine, Clopidogrel, and Prasugrel in Humans

Abstract

Ticlopidine, clopidogrel, and prasugrel are thienopyridine prodrugs that inhibit adenosine-5'-diphosphate (ADP)-mediated platelet aggregation in vivo. These compounds are converted to thiol-containing active metabolites through a corresponding thiolactone. The 3 compounds differ in their metabolic pathways to their active metabolites in humans. Whereas ticlopidine and clopidogrel are metabolized to their thiolactones in the liver by cytochromes P450, prasugrel proceeds to its thiolactone following hydrolysis by carboxylesterase 2 during absorption, and a portion of prasugrel's active metabolite is also formed by intestinal CYP3A. Both ticlopidine and clopidogrel are subject to major competing metabolic pathways to inactive metabolites. Thus, varying efficiencies in the formation of active metabolites affect observed effects on the onset of action and extent of inhibition of platelet aggregation (IPA). Knowledge of the CYP-dependent formation of ticlopidine and clopidogrel thiolactones helps explain some of the observed drug-drug interactions with these molecules and, more important, the role of CYP2C19 genetic polymorphism on the pharmacokinetics of and pharmacodynamic response to clopidogrel. The lack of drug interaction potential and the absence of CYP2C19 genetic effect result in a predictable response to thienopyridine antiplatelet therapy with prasugrel. Current literature shows that greater ADP-mediated IPA is associated with significantly better clinical outcomes for patients with acute coronary syndrome.

Biotransformation of Prasugrel, a Novel Thienopyridine Antiplatelet Agent, to the Pharmacologically Active Metabolite

“…Prasugrel has been shown to reduce the rate of thrombotic cardiovascular events and stent thrombosis in patients with acute coronary syndrome that are undergoing percutaneous coronary intervention (Wiviott et al, 2007) (Effient package insert). The thienopyridines are prodrugs that are converted in vivo to their pharmacologically active metabolites that possess a thiol group via a corresponding thiolactone metabolite (Farid et al, 2010). However, with the exception of an oxidation step catalyzed by cytochrome P450 (Savi et al, 1994;Rehmel et al, 2006), the mechanism for the active metabolite formation from thienopyridines remained unknown until recently reported for ticlopidine and clopidogrel (Dansette et al, 2009).…”

Acute Coronary Syndrome: Focus on Antiplatelet Therapy

“…9 Clopidogrel and prasugrel are both orally administered, thienopyridine-based, irreversibly binding P2Y 12 inhibitors, which must be converted into an active metabolite to allow binding to the P2Y 12 receptor. 10 Ticagrelor, an orally administered, reversibly binding P2Y 12 receptor antagonist, is the first in a new class of agents, cyclopentyltriazolopyrimidines, and does not need a metabolic conversion step to become active. In addition to P2Y 12 inhibition, ticagrelor also increases extracellular adenosine levels by inhibiting the equilibrative nucleoside transporter-1.…”

The Pharmacogenetics of Cardiovascular Drugs / FARMAKOGENETIKA KARDIOVASKULARNIH LEKOVA

“…CYP2C19 is the primary isoform responsible for clopidogrel activation (16). Carriers of loss of function alleles CYP2C9*2 and CYP2C9*3 have impaired ability to metabolize clopidogrel.…”