Changes in plasma and urinary 11-dehydrothromboxane B2 in healthy subjects produced by oral CS-518, a novel thromboxane synthase inhibitor.
When 50 mg CS-518, a novel thromboxane (TX) A2 synthase inhibitor, was orally administered to healthy male volunteers, the plasma concentration of CS-518 peaked after 0.5 h and then decreased with a half-life of 0.44 h. There was no significant change in the plasma concentration of circulating TXB2, whereas that of circulating 11-dehydrothromboxane B2 (11-dhTXB2), an enzymatic metabolite of TXB2, was significantly decreased from 0.5 h to 24 h after administration; the maximal decrease to about 25% of the pre-dose value was found at 6 h. After CS-518 100 mg b.d. for 4.5 days, plasma 11-dhTXB2 was suppressed to the same extent as after the single dose of 50 mg from 6 h after the initial dose throughout the administration period. The urinary excretion of 11-dhTXB2 corrected for the creatinine level was significantly decreased by 70-84% throughout the treatment. These results suggest that CS-518 causes long-lasting inhibition of TXA2 synthase despite its rapid elimination from plasma, and that circulating 11-dhTXB2 in plasma and its urinary excretion can serve as a quantitative index of TXA2 synthase inhibition in vivo by CS-518.
Uematsu
T
T
Department of Pharmacology, Hamamatsu University School of Medicine, Japan.
Takasaki
W
W
Kosuge
K
K
Wada
K
K
Matsuno
H
H
Tanaka
Y
Y
Yamamura
N
N
Nakashima
M
M
D000284:Administration, Oral; D000328:Adult; D006207:Half-Life; D006801:Humans; D008297:Male; D013876:Thiophenes / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000652:urine; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors* / Q000097:blood
D013876:Thiophenes; C055806:RS 5186; D013929:Thromboxane B2; C049235:11-dehydro-thromboxane B2; D013930:Thromboxane-A Synthase