Enantioselective pharmacodynamics of the nonsteroidal antiinflammatory drug ketoprofen: In vitro inhibition of human platelet cyclooxygenase activity

Abstract

The pharmacological activity of ketoprofen enantiomers was investigated in humans by an in vitro method. The antiplatelet effect of ketoprofen was assessed by measuring the inhibition of platelet thromboxane B₂ (TXB₂) generation during the controlled clotting of whole blood obtained from each of four healthy volunteers. Ketoprofen was added separately to whole blood as a range of concentrations of (1) predominantly (S)-ketoprofen, (2) racemic ketoprofen, and (3) predominantly (R)-ketoprofen. (S)-Ketoprofen was found to be solely active at inhibiting human platelet TXB₂ production; (R)-ketoprofen was devoid of such activity and did not modify the potency of its optical antipode. A relationship between the percentage inhibition of TXB₂ generation and the unbound concentration of (S)-ketoprofen in serum was modelled according to a sigmoidal E_max equation. The mean (±SD) serum unbound concentration of (S)-ketoprofen required to inhibit platelet TXB₂ generation by 50% (EC₅₀) was 0.320 (±0.062) ng/ml. This value for ketoprofen is considerably lower than previously reported values for (S)-ibuprofen and (S)-naproxen.