RT Journal Article
SR Electronic
T1 Biomarker Optimization to Track the Antithrombotic and Hemostatic Effects of Clopidogrel in Rats
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 369
OP 377
DO 10.1124/jpet.106.119156
VO 322
IS 1
A1 William A. Schumacher
A1 Jeffrey S. Bostwick
A1 Martin L. Ogletree
A1 Anne B. Stewart
A1 Thomas E. Steinbacher
A1 Ji Hua
A1 Laura A. Price
A1 Pancras C. Wong
A1 Robert P. Rehfuss
YR 2007
UL http://jpet.aspetjournals.org/content/322/1/369.abstract
AB We determined the dose response of the ADP antagonist clopidogrel (0.3-50 mg/kg p.o.) in rat models of thrombosis and provoked bleeding and correlated these activities to ex vivo platelet activation. Carotid artery thrombosis was induced by FeCl2. Bleeding time was measured by mesenteric vessel puncture and renal cortex or cuticle incision. Platelet biomarkers included standard ADP-induced aggregation, P2Y12 receptor occupancy, and phosphorylation of vasodilator-stimulated phosphoprotein. Clopidogrel decreased thrombus weight up to 78%, caused maximal prolongation of cuticle and mesenteric bleeding, but had little effect on renal bleeds. Due to the steep mesenteric dose response, further comparisons concentrated on cuticle bleeding. The half-maximal inhibitory dose (ED50) for thrombus reduction was 2.4 ± 0.4 mg/kg, with 10 mg/kg providing optimal blood flow preservation and thrombus reduction. The ED50 for bleeding was 10.5 ± 3.4 mg/kg. Increased bleeding was intermediate (3-fold) at 10 mg/kg and maximal (6-fold) at 30 mg/kg. All biomarkers were affected, but with differing sensitivity. ED50s for peak platelet aggregation to 10 μM ADP (11.9 ± 0.4 mg/kg) and the vasodilator-stimulated phosphoprotein index (16.4 ± 1.3 mg/kg) approximated the higher ED50 for bleeding. ED50s for ligand binding (3.0 ± 0.3 mg/kg) and late aggregation (5.1 ± 0.4 mg/kg) better matched the lower ED50 for antithrombotic activity. Aspirin exerted lesser effects on bleeding (42-70% increase in all models) and thrombosis (24% inhibition). In summary, antithrombotic doses of clopidogrel have limited effects on bleeding and standard measures of platelet aggregation. Other biomarkers may be more sensitive for tracking antithrombotic efficacy. The American Society for Pharmacology and Experimental Therapeutics