title: Determinants of subacute response to clopidogrel: relative impact of CYP2C19 genotype and PGE1/adenylate cyclase signalling.
abstract: BACKGROUND
  and
  
  
  OBJECTIVE
  The signal transduction pathway modulated by activation or blockade of platelet P2Y12 receptors is linked to PGE1-stimulated adenylate cyclase effects, but this link's impact on P2Y12 receptor antagonist response is uncertain. We therefore tested the hypothesis that pre-treatment platelet responsiveness to PGE1 predicts subsequent responsiveness to clopidogrel.
  
  
  METHODS
  In order to maximise heterogeneity of platelet responsiveness to PGE1 we investigated both healthy subjects (n=30) and patients with CHD undergoing elective coronary stenting (n=22), all genotyped for common CYP2C19 variants associated with clopidogrel sensitivity (CS). We determined baseline pre-clopidogrel platelet sensitivity to the inhibitory effects of PGE1 by ADP-induced whole blood aggregation. Clopidogrel was administered for 7days utilising a weight-based regimen. CS was expressed as change (Δ) in ADP-induced aggregation and in VASP-phosphorylation (VASP-P). We used univariate and multivariate analysis to correlate such parameters with PGE1 sensitivity, BMI and presence/absence of CHD.
  
  
  RESULTS
  In the study cohort, pre-treatment responsiveness to PGE1 varied widely (70±28 [standard deviation (SD)]% inhibition of aggregation: range 10 to 100%). In the entire study cohort, pre-treatment PGE1 sensitivity correlated with CS irrespective of genotype. On univariate analysis, CS was not significantly greater for patients without than those with loss-of-function mutations. Moreover, at multivariate analysis, PGE1 sensitivity, but not genotype, was a strong correlate of ΔADP and ΔVASP-P (P<0.0001 for both).
  
  
  CONCLUSIONS
  The integrity of the cAMP pathway is a major determinant of subacute CS.
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: Nicola L
authors.initials: NL
authors.lastname: Hurst
authors.affiliation: Department of Cardiology and Pharmacology, The Queen Elizabeth Hospital, Woodville South, Australia; University of South Australia, Basil Hetzel Institute, Woodville South, Australia.
authors.forename: Vivek B
authors.initials: VB
authors.lastname: Nooney
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: Yuliy Y
authors.initials: YY
authors.lastname: Chirkov
authors.affiliation: Institute of Cardiology and Centre of Excellence on Aging, "G. d'Annunzio" University-Chieti, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Caterina
authors.affiliation: Department of Cardiology and Pharmacology, The Queen Elizabeth Hospital, Woodville South, Australia; The University of Adelaide, Basil Hetzel Institute, Woodville South, Australia; University of South Australia, Basil Hetzel Institute, Woodville South, Australia. Electronic address: john.horowitz@adelaide.edu.au.
authors.forename: John D
authors.initials: JD
authors.lastname: Horowitz
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000527:Alprostadil / Q000378:metabolism*; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D000262:Adenylyl Cyclases; D000527:Alprostadil; D013988:Ticlopidine
keywords: adenylate cyclase; blood platelets; clopidogrel; cyclic AMP; purinergic P2Y(12) receptor antagonists