Pharmacokinetic and pharmacodynamic differences between two low dosages of aspirin may affect therapeutic outcomes

Background: Meta-analyses of the prevention of major vascular events by aspirin suggest therapeutic equivalence of all dosages. However, the optimal dosage still remains problematic, and a recent trial found aspirin 160 mg/day to be more effective than 80 mg/day for secondary prevention of ischaemic stroke. Objective: To evaluate two low dosages of aspirin in terms of pharmacokinetics and pharmacodynamics (inhibition of platelet thromboxane generation and urinary excretion of thromboxane and prostacyclin metabolites). Design and Participants: A randomised cross-over study was performed in 16 healthy volunteers (9 women and 7 men, 33.8 +/- 5.1 years old) given enteric-coated aspirin 80 or 160 mg/day for 7 days. Methods: Plasma concentrations of salicylate and aspirin were measured by high-performance liquid chromatography (HPLC) after both the first and the last dose (days 1 and 7). The usual pharmacokinetic parameters were then derived. Serum thromboxane B-2 (TxB(2)) was measured by radioimmunoassay. The urinary excretion of 11-dehydro-TxB(2) and 2,3-dinor-6-keto-prostaglandin F-1alpha were measured on 8-hour urine samples by immunoassay after extraction and HPLC separation, both before and after 7 days of drug administration. Results: With the 160mg dosage, but not with the 80mg dosage, higher concentrations of aspirin were found at day 7 compared with day 1: For aspirin 80 mg/day, 24-hour area under the concentration-time curve (AUC(24)) was similar on days 1 and 7 (569 +/- 339 vs 605 +/- 377 mug . h/L), but increased from 904 +/- 356 mug . h/L on kday 1 to 1355 +/- 883 mug . h/L on day 7 with the higher dosage. Similarly, the AUC(24) for salicylate was similar on days 1 and 7 with the lower dosage, but significantly increased from day 1 to day 7 after the higher dosage. This paralleled inhibition of serum TxB(2) levels (99% vs 95% average inhibition by 160 and 80 mg/day) and of urinary excretion of thromboxane metabolite (77% vs 61% average inhibition by 160 and 80 mg/day), without altering the excretion of prostacyclin metabolite. Conclusions: Inhibition of serum TxB(2) generation and of thromboxane metabolite urinary excretion-by the lower, dosage of aspirin, although substantial, still appeared incomplete. The small but significant further increase of serum TxB(2) inhibition by the higher dosage was accompanied by an even greater inhibition of urinary excretion. We suggest that in some instances this difference would translate into a greater clinical benefit with the higher aspirin dosage. Our findings may also contribute to better definition of the recent concept of 'aspirin resistance'.