title: Reappraisal of the clinical pharmacology of low-dose aspirin by comparing novel direct and traditional indirect biomarkers of drug action.
abstract: BACKGROUND
  Even though the acetylation of platelet cyclooxygenase (COX)-1 at serine-529 is the direct mechanism of action of low-dose aspirin, its antiplatelet effect has been characterized using indirect indexes of COX-1 activity.
  
  
  OBJECTIVE
  We performed a clinical study with enteric-coated low-dose aspirin (EC-aspirin), in healthy subjects, to evaluate the effects on the extent and duration of platelet COX-1 acetylation, using a novel proteomic strategy for absolute protein quantification (termed AQUA), as compared with traditional pharmacokinetic and pharmacodynamic parameters.
  
  
  METHODS
  In a phase I, single-arm, open-label study of EC aspirin (100 mg day(-1) ) administered to 24 healthy subjects, we compared, over a 24 h-period on day 1 and 7, % platelet acetylated COX-1 (AceCOX-1) with traditional pharmacokinetic and pharmacodynamics [i.e. serum thromboxane (TX) B2 , platelet function by monitoring CEPI(collagen/epinephrine) closure time (CT) using whole-blood PFA-100 and urinary excretion of 11-dehydro-TXB2 ] parameters.
  
  
  RESULTS
  Acetylation of platelet COX-1 was measurable before detection of aspirin levels in the systemic circulation and increased in a cumulative fashion upon repeated dosing. After the last dose of EC-aspirin, %AceCOX-1, serum TXB2 and CEPI-CT values were maximally and persistently modified throughout 24 h; they averaged 76 ± 2%, 99.0 ± 0.4% and 271 ± 5 s, respectively. EC-aspirin caused 75% reduction in urinary 11-dehydro-TXB2 excretion. After chronic dosing with aspirin, the pharmacokinetics of acetylsalicylic acid was completely dissociated from pharmacodynamics.
  
  
  CONCLUSIONS
  The demonstrated feasibility of quantifying the extent and duration of platelet COX-1 acetylation will allow characterizing the genetic, pharmacokinetic and pharmacodynamic determinants of the inter-individual variability in the antiplatelet response to low-dose aspirin as well as identifying extra-platelet sites of drug action.
authors.affiliation: Section of Cardiovascular and Pharmacological Sciences, Department of Neuroscience, Imaging and Clinical Science, Center of Excellence on Aging (CeSI), 'G. d'Annunzio' University, Chieti, Italy; Center of Excellence on Aging (CeSI), "G. d'Annunzio" University, Chieti, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Patrignani
authors.forename: S
authors.initials: S
authors.lastname: Tacconelli
authors.forename: E
authors.initials: E
authors.lastname: Piazuelo
authors.forename: L
authors.initials: L
authors.lastname: Di Francesco
authors.forename: M
authors.initials: M
authors.lastname: Dovizio
authors.forename: C
authors.initials: C
authors.lastname: Sostres
authors.forename: E
authors.initials: E
authors.lastname: Marcantoni
authors.forename: P
authors.initials: P
authors.lastname: Guillem-Llobat
authors.forename: P
authors.initials: P
authors.lastname: Del Boccio
authors.forename: M
authors.initials: M
authors.lastname: Zucchelli
authors.forename: C
authors.initials: C
authors.lastname: Patrono
authors.forename: A
authors.initials: A
authors.lastname: Lanas
mesh_terms: D000107:Acetylation; D019540:Area Under Curve; D001241:Aspirin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood*; D051545:Cyclooxygenase 1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D013929:Thromboxane B2 / Q000097:blood
chemical_list: D015415:Biomarkers; D013929:Thromboxane B2; D051545:Cyclooxygenase 1; D001241:Aspirin
keywords: 11-dehydro-thromboxane B2; acetylsalicylic acid; antiplatelet drugs; cyclooxygenase-1; proteomics; thromboxane A2