title: Clopidogrel "resistance": pre- vs post-receptor determinants.
abstract: The clinical efficacy of the P2Y12 receptor antagonist clopidogrel as an agent to prevent thrombotic events predominantly reflects its anti-aggregatory effects. Stent thrombosis in particular is more likely to occur in patients in whom clopidogrel effect is limited. "Resistance" to clopidogrel in general should theoretically arise either because of a reduction in plasma concentration of the active metabolite and/or of the downstream intracellular biochemical changes underlying antiplatelet effects. We therefore postulate that "resistance" to clopidogrel arises via a combination of pharmacogenetic, pharmacokinetic and intracellular biochemical mechanisms. Considerable attention has been so far directed to the finding that stent thrombosis occurs more frequently in patients with loss-of-function mutations of CYP2C19, thus limiting clopidogrel bioactivation. Furthermore, a number of drug-drug interactions may marginally impair responsiveness to clopidogrel, largely via impairment of bioactivation. However, population data also suggest that clopidogrel "resistance" occurs more frequently in patients with acute coronary syndromes than in normal subjects, and that "resistance" is particularly common in obese subjects and with diabetes. Here we critically review available literature and speculate on the possibility that non-genetic causes of clopidogrel "resistance" may arise from impairments of the intracellular signaling cascade initiated by P2Y12 receptor inhibition. In such cases, "resistance" to clopidogrel may also theoretically occur with other P2Y12 receptor antagonists, irrespective of the need for bioactivation. Delineation of this non-genetic component of "resistance" to P2Y12 inhibitors may facilitate the development of optimal therapeutic strategies for high-risk cardiovascular patients.
authors.affiliation: Department of Cardiology and Pharmacology, The Queen Elizabeth Hospital, Woodville South, Australia; The University of Adelaide, Basil Hetzel Institute, Woodville South, Australia.
authors.forename: N L
authors.initials: NL
authors.lastname: Hurst
authors.forename: V B
authors.initials: VB
authors.lastname: Nooney
authors.forename: B
authors.initials: B
authors.lastname: Raman
authors.forename: Y Y
authors.initials: YY
authors.lastname: Chirkov
authors.forename: R
authors.initials: R
authors.lastname: De Caterina
authors.forename: J D
authors.initials: JD
authors.lastname: Horowitz
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D004347:Drug Interactions; D004351:Drug Resistance; D006801:Humans; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology; D015398:Signal Transduction; D015607:Stents; D013927:Thrombosis / Q000209:etiology / Q000517:prevention & control*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D010975:Platelet Aggregation Inhibitors; D058920:Purinergic P2X Receptor Antagonists; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine
keywords: Anti-platelet agents; Clopidogrel; P2Y(12) inhibitors; Platelets; Thrombosis