Effective antiplatelet drug concentrations in experimental arterial thromboembolism.
Although drugs that modify platelet function have been widely studied as antithrombotic agents in experimental and clinical studies, there is limited information regarding the relationship between in vivo drug blood concentrations and antithrombotic efficacy. This study compared the pharmacokinetics of three antiplatelet agents with their antithrombotic effects in an experimental model of arterial thromboembolism in baboons. Thrombus formation was measured as steady-state platelet utilization induced by thrombogenic arteriovenous cannulae. The drugs studied were aspirin, dipyridamole and sulfinpyrazone. Aspirin was administered in daily doses of 20 mg/kg, dipyridamole in daily doses of 2.5 and 10 mg/kg, and sulfinpyrazone in daily doses of 20 and 100 mg/kg; each drug was given in two equal doses per day. Multiple blood samples were collected for drug analysis after steady-state had been reached. The average concentrations of dipyridamole at steady-state were 26 +/- 15 and 79 +/- 69 ng/ml after 2.5 and 10 mg/kg/day. These concentrations were associated with 28 and 87% inhibition of cannula platelet consumption, respectively. The average steady-state concentrations of acetylsalicylic and salicylic acids were 0.67 +/- 0.80 and 3.76 +/- 2.60 micrograms/ml, respectively, after 20 mg/kg/day. Aspirin had no effect on platelet consumption. Average concentrations of sulfinpyrazone were 1.05 +/- 0.45 and 12.25 +/- 5.73 micrograms/ml after 20 and 100 mg/kg/day, with significant concentrations of the sulfide metabolite. These concentrations were associated with 23 and 85% inhibition of platelet consumption, respectively. No significant pharmacokinetic interactions were observed after concurrent administration of aspirin and dipyridamole or sulfinpyrazone. As the experimental model used involves thrombus formation on an artificial surface, it is likely that these results are most relevant to patients with arterial prosthetic devices.
Department of Medicine, Duke University Medical Center, Durham, North Carolina.
T D
TD
Bjornsson
S R
SR
Hanson
L A
LA
Harker
D000818:Animals; D001166:Arteriovenous Shunt, Surgical; D001241:Aspirin / Q000097:blood / Q000627:therapeutic use*; D004176:Dipyridamole / Q000097:blood / Q000627:therapeutic use*; D007700:Kinetics; D008297:Male; D010215:Papio; D013442:Sulfinpyrazone / Q000097:blood / Q000627:therapeutic use*; D013923:Thromboembolism / Q000097:blood* / Q000188:drug therapy
D004176:Dipyridamole; D001241:Aspirin; D013442:Sulfinpyrazone