抄録
Low-dose aspirin inhibits cyclooxygenase-1 (COX-1) on platelets irreversibly, suppressing platelet aggregation.Nonsteroidal anti-inflammatory drugs (NSAIDs) also inhibit COX-1 reversibly by forming a salt bridge. However, there is little information on the antiplatelet effects of the chronic use of NSAIDs (other than aspirin). We performed pharmacokinetics/pharmacodynamics (PK/PD) analysis using in vitro experimental data obtained when NSAIDs were added to human blank blood, and estimated the antiplatelet effects of continuous NSAID administration.
Ibuprofen, diclofenac, indomethacin and loxoprofen were studied in a one-compartment model, and etodolac was studied in a two-compartment model. Platelet aggregation was measured after adding NSAIDs to platelet-rich plasma at a range of concentrations containing the maximum plasma concentrations of one clinical dose. We calculated the platelet-aggregation threshold index (PATI) as an index of aggregation activity, which was defined as the putative stimulus concentration giving 50% aggregation, and performed PD analysis according to the sigmoidal Emax model. Simulated time-PATI curves of NSAIDs were compared to that of low-dose aspirin.
Simulated values of increase in PATI for the maximum plasma concentration of each NSAID were lower than 3.9 µg/mL, which is the same as that of low-dose aspirin. Increases in PATI around the trough concentration were nearly zero for all NSAIDs except ibuprofen, thus suggesting that the antiplatelet effects of continuous NSAID administration are weaker and less persistent than those of low-dose aspirin. The simulation results indicate that continuous NSAID administration is less effective at preventing thrombosis and embolism than low-dose aspirin, and postoperative NSAID treatment needs to be careful of the occurrence of bleeding.
