Effects of racemic, S- and R-indobufen on cyclooxygenase and lipoxygenase activities in human whole blood.

Racemic indobufen inhibits human platelet aggregation by reducing thromboxane (TX) A2 biosynthesis. In order to ascertain which of the two optical isomers is responsible for its pharmacological activity, we compared the effects of racemic (SR +/-), S(+) enantiomer and R(-) enantiomer indobufen on cyclooxygenase and 5-lipoxygenase activities by assessing the biosynthesis of TXB2, prostaglandin (PG) E2 and leukotriene (LT) B4 in human whole blood stimulated with the Ca2+ ionophore A23187. Racemic indobufen caused a dose-dependent inhibition of TXB2 and PGE2 production (IC50: 0.53 +/- 0.06 and 0.34 +/- 0.02 micrograms/ml, respectively; mean +/- S.D., n = 4). S-Indobufen was approximately 2-fold more potent than the racemate in inhibiting the synthesis of cyclooxygenase products. R-Indobufen affected the same enzyme but only at considerably higher concentrations (IC50: 53 +/- 8 micrograms/ml, n = 3). Serum LTB4 concentrations were significantly reduced only at indobufen concentrations greater than 50 micrograms/ml. In conclusion, indobufen is a selective inhibitor of the cyclooxygenase activity of platelet PGG/H synthase in a concentration range corresponding to the therapeutic plasma levels in man. This inhibitory effect is largely due to the S isomer of the drug.