Disposition and effect of the new thromboxane synthetase inhibitor 6-(1-imidazolylmethyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid in man.
The disposition of a new thromboxane synthetase inhibitor, 6-(1-imidazolylmethyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (DP-1904) upon administration of a single 200-mg oral dose to normal Japanese volunteers was studied. DP-1904 proved to be rapidly absorbed from the gastrointestinal tract and converted to its ester glucuronide, which appeared in plasma within 30 min after dosing. The AUCs of DP-1904 and its ester glucuronide were 7.23 +/- 0.54 and 7.93 +/- 0.86 micrograms.h/ml (mean +/- S.E., n = 5), respectively. Both compounds were also eliminated very rapidly from the body (half-lives greater than 60 min). The primary route of elimination was renal, with 52.1 +/- 2.2 and 37.6 +/- 1.6% of the dose being excreted in the urine as the unchanged form and the glucuronide conjugate within 48 h, respectively. The cumulative fecal excretion rates of DP-1904 up to 48 h after dosing were approximately 0.5%. The main metabolite of DP-1904 in humans was DP-1904 glucuronide. Serum thromboxane (TX) B2 levels were reduced more than 98% within 1 h after dosing. There was still more than 75% suppression of serum TXB2 levels at 12 h after dosing. At 72 h TXB2 concentrations returned to control levels. These data indicate that DP-1904 is a potent and long-acting thromboxane synthetase inhibitor.
Drug Metabolism and Analytical Chemistry Research Center, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
M
M
Tanaka
K
K
Ono
H
H
Hakusui
T
T
Takegoshi
T
T
Shiozawa
S
S
Nii
H
H
Shibata
D000328:Adult; D005243:Feces / Q000032:analysis; D006207:Half-Life; D006801:Humans; D007093:Imidazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D008297:Male; D009281:Naphthalenes / Q000493:pharmacokinetics*; D013764:Tetrahydronaphthalenes / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D013929:Thromboxane B2 / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D007093:Imidazoles; D009281:Naphthalenes; D013764:Tetrahydronaphthalenes; D013929:Thromboxane B2; C056295:nafagrel; D013930:Thromboxane-A Synthase