PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSIS OF A NOVEL LEUKOTRIENE BIOSYNTHESIS INHIBITOR, MK-0591, IN HEALTHY-VOLUNTEERS

1 The pharmacokinetic and pharmacodynamic properties of a novel 2-indo lealkanoic acid derivative (MK-0591), a potent inhibitor of leukotrien e biosynthesis, were investigated in healthy male Japanese volunteers. Single oral doses of 50, 125, 250 and 500 mg and multiple oral doses of 125 mg twice daily for 9.5 days and 250 mg once daily for 10 days w ere administered. 2 After the single-dose administration following ove rnight fasting, C-max and AUC of MK-0591 in plasma increased in a dose -dependent manner, while elimination half-life remained constant (11.2 -13.2 h) irrespective of dose. Food intake decreased C-max and AUC by 71% and 68%, respectively, at a dose of 250 mg. With respect to multip le-dose administration before meals, there were no significant differe nces in the pharmacokinetic parameters between the first and last days , indicating a lack of significant accumulation of MK-0591 in plasma. Urinary recovery as the unchanged form was negligible throughout the s tudy. 3 Ionophore-stimulated production of leukotriene B-4 (LTB(4)) in blood ex vivo was inhibited significantly from 1 h until 12 to 48 h a fter single-dose administration as compared with predose value. In par allel, the urinary excretion of endogenous leukotriene E(4) (LTE(4)) w as significantly decreased from 4 to 8 h until 48 to 72 h after drug a dministration. Reduction of ionophore-stimulated LTB(4) biosynthesis a nd urinary excretion of LTE(4) following single administration of MK-0 591 was statistically significant as compared with placebo group, and the duration of inhibition of LTB(4) biosynthesis was dose-related. Th ere was no attenuation of pharmacological effect in association with r epeated doses of MK-0591. 4 At the highest single dose and during the multiple doses, transient, mild to moderate gastrointestinal side effe cts such as abdominal discomfort or pain and soft stools or diarrhoea that were tolerated without any treatment were encountered.