Aspirin Extrusion From Human Platelets Through Multidrug Resistance Protein-4-Mediated Transport: Evidence of a Reduced Drug Action in Patients After Coronary Artery Bypass Grafting
JACC - Journal of the American College of Cardiology, 08/12/2011Mattiello T et al.
Aspirin is a substrate for MRP4 and can be extruded from platelet through its transportation. Aspirin effect on COX–1 is little–related to MRP4–mediated aspirin transport in HV, but in CABG patients with MRP4 over–expression, its pharmacological inhibition enhances aspirin action in an efficient way.
Intracellular aspirin concentration and drug COX–1 activity, measured by thrombin–induced thromboxane B2 (TxB2) production, were evaluated in platelets obtained from healthy volunteers (HV) and hematopoietic–progenitor cell cultures reducing or not reducing MRP4–mediated transport.
Platelet MRP4 expression was evaluated, in platelets from HV and CABG patients, by dot–blot or by immunogold–electromicrographs or immunofluorescence–microscopy analysis.
Inhibition of MRP4–mediated transport by dipyridamole or Mk–571 increases aspirin entrapment and its in vitro effect on COX–1 activity (142.7 ± 34.6 pg/108 cells vs. 343.7 ± 169.3 pg/108 cells TxB2–production).
Platelets derived from megakaryocytes transfected with MRP4 small interfering ribonucleic acid have a higher aspirin entrapment and drug COX–1 activity.
Platelets from CABG patients showed a high expression of MRP4 whose in vitro inhibition enhanced aspirin effect on COX–1 (349 ± 141 pg/108 cells vs. 1,670 ± 646 pg/108 cells TxB2–production).
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