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-indolealkanoic acid derivative (MK-0591), a potent inhibitor of leukotriene 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 were administered. 2. After the single-dose administration following overnight fasting, Cmax 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 Cmax and AUC by 71% and 68%, respectively, at a dose of 250 mg. With respect to multiple-dose administration before meals, there were no significant differences 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 study. 3. Ionophore-stimulated production of leukotriene B4 (LTB4) in blood ex vivo was inhibited significantly from 1 h until 12 to 48 h after single-dose administration as compared with predose value. In parallel, the urinary excretion of endogenous leukotriene E4 (LTE4) was significantly decreased from 4 to 8 h until 48 to 72 h after drug administration. Reduction of ionophore-stimulated LTB4 biosynthesis and urinary excretion of LTE4 following single administration of MK-0591 was statistically significant as compared with placebo group, and the duration of inhibition of LTB4 biosynthesis was dose-related.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Pharmacology, Hamamatsu University School of Medicine, Japan.
T
T
Uematsu
M
M
Kanamaru
K
K
Kosuge
K
K
Hara
N
N
Uchiyama
N
N
Takenaga
W
W
Tanaka
B S
BS
Friedman
M
M
Nakashima
D000284:Administration, Oral; D000328:Adult; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004435:Eating; D005215:Fasting; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D007564:Japan; D007975:Leukotriene B4 / Q000096:biosynthesis / Q000097:blood; D017999:Leukotriene E4 / Q000096:biosynthesis / Q000652:urine; D016859:Lipoxygenase Inhibitors / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D011804:Quinolines / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology
D007211:Indoles; D016859:Lipoxygenase Inhibitors; D011804:Quinolines; C078266:MK 0591; D007975:Leukotriene B4; D017999:Leukotriene E4