The pharmacokinetics and pharmacodynamics of a new thromboxane synthetase inhibitor, 6-(1-imidazolylmethyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (DP-1904) in man after repeated oral doses.
The pharmacokinetics of DP-1904, a new potent and selective thromboxane synthetase inhibitor, and its effects on ex-vivo prostanoid formation have been studied in groups of Japanese normal male volunteers, who received repeated oral doses of 200 mg every 12 h for 4 doses, or 400 mg every 24 h for 2 doses, or 200 mg every 12 h for 14 doses. The drug was well tolerated by all subjects without evidence of adverse reactions. Repeated administration showed no significant changes in half-lives, tmax values, cmax values and AUC values. DP-1904 did not exhibit time-dependent kinetics. Its plasma levels were lower than the quantifiable level (50 ng mL-1) at 12 h after each dose. These data suggest no significant accumulation of DP-1904 in normal volunteers. DP-1904 reduced the serum thromboxane B2 by about 80% during the medication, the serum concentrations returning to about 44, 75 and 20% of the predrug control values at 36 h after the last 200 mg doses and 48 h after the last 400 mg dose.
Tanaka
M
M
Drug Metabolism and Analytical Chemistry Research Center, Daiichi Pharmaceutical Co. Ltd., Tokyo, Japan.
Ono
K
K
Hakusui
H
H
Takegoshi
T
T
Shiozawa
T
T
Suzuki
T
T
Nii
S
S
Shibata
H
H
D000284:Administration, Oral; D000328:Adult; D002851:Chromatography, High Pressure Liquid; D006207:Half-Life; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D008657:Metabolic Clearance Rate; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D013929:Thromboxane B2 / Q000096:biosynthesis / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D007093:Imidazoles; D013764:Tetrahydronaphthalenes; D013929:Thromboxane B2; C056295:nafagrel; D013930:Thromboxane-A Synthase