PHARMACOKINETICS AND PHARMACODYNAMICS OF MULTIPLE ORAL DOSES OF MK-0591, A 5-LIPOXYGENASE-ACTIVATING PROTEIN INHIBITOR

The pharmacodynamics, kinetics, and tolerability of a new orally active 5-lipoxygenase inhibitor were evaluated in healthy male volunteers. MK-0591, 50, 125, and 250 mg every morning and 250 mg every 12 hours, was administered for 10 days. Leukotriene B-4 biosynthesis ex vivo in ionophore (A23187)stimulated whole blood and leukotriene E(4) levels in urine were determined. Leukotriene B, production was inhibited up to 90% of baseline for 12 hours after administration at the highest dose. The degree of leukotriene B-4 inhibition ex vivo in whole blood significantly correlated with plasma MK-0591 concentrations (0 to 1500 ng/ml; r = 0.73). Urinary leukotriene E(4) was inhibited by > 80% at 24 hours after administration for all dose levels. Pharmacokinetics of MR-0591 were linear, with a half-life of approximately 6 hours. Very little accumulation was seen after multiple dosing. MR-0591 had no effect on testosterone levels, and good tolerability was shown at all dose levels of MK-0591 administered for up to 10 days.