Lipoxygenase inhibitory activity of U-66,858 and its deacetylated metabolite U-68,244 in human whole blood.

The inhibitory effects of the semi-quinone U-66,858 and its metabolite U-68,244 on the ionophore-induced formation of leukotriene B4 (LTB4) were examined in human whole blood (WB). Preincubation of U-66,858 and U-68,244 for 1 min prior to challenge of blood with calcium ionophore A23187 resulted in IC50 values of 1080 +/- 644 and 820 +/- 442 nmol/L, respectively (NS). After 60 min preincubation, values were 250 +/- 85 and 270 +/- 79 nmol/L (NS). The activity of the lipoxygenase inhibitor AA-861 in this system was similar to that of U-66,858, while vitamin K and the sulphate conjugate of U-66,858 showed significant inhibition of LTB4 release only at micromolar concentrations. U-66,858 exhibited significant inhibition of thromboxane A2 release (p < 0.02) in a comparative study with the known cyclooxygenase (CO) inhibitor flurbiprofen. The metabolism of U-66,858 in contact with WB at 37 degrees C was monitored for 70 min using [14C]-labelled drug and reverse-phase HPLC, the majority of recovered radioactivity no longer in the form of U-66,858 being accounted for by U-68,244 and polar conjugates of U-66,858. Thus, U-66,858 is a potent inhibitor of LTB4 production in human whole blood and undergoes deacetylation to an initial metabolite with similar pharmacological potency. However, other metabolites of U-66,858 such as the sulphate conjugate, are relatively weak inhibitors of 5-lipoxygenase (5-LO) under similar conditions.