Changes in plasma and urinary 11-dehydrothromboxane B2 in healthy subjects produced by oral CS-518, a novel thromboxane synthase inhibitor
- 20 Downloads
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.
Key wordsThromboxane synthase inhibitor CS-518 11-dehydrothromboxane B2 enzyme immunoassay thromboxane B2
Unable to display preview. Download preview PDF.
- 1.Moncada S, Vane JR (1979) Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane A2 and prostacyclin. Pharmacol Rev 30: 293–331Google Scholar
- 2.Lewy RI, Wiener L, Walinsky P, Lefer AM, Silver MJ, Smith JB (1980) Thromboxane release during pacing-induced angina pectoris: Possible vasoconstrictor influence on the coronary vasculature. Circulation 61: 1165–1171Google Scholar
- 3.Cairns JA, Gent M, Singer J, Finnie KJ, Froggatt GM, Holder DA, Jablonsky G, Kostuk WJ, Melendez LJ, Myers MG, Sackett DL, Sealey BJ, Tanser PH (1985) Aspirin, sulfinpyrazone, or both in unstable angina. Results of a Canadian multicenter trial. N Engl J Med 313: 1369–1375Google Scholar
- 4.Klimt CR, Knatterud GL, Stamler J, Meier P (1986) Persantineaspirin reinfarction study. II. Secondary coronary prevention with persantine and aspirin. J Am Coll Cardiol 7: 251–269Google Scholar
- 5.Uematsu T, Nagashima S, Mizuno A, Inaba H, Kosuge K, Nakashima M (1993) Pharmacokinetic and pharmacodynamic profiles of CS-518, a selective, long-lasting thromboxane synthase inhibitor after single and multiple oral administration to healthy volunteers. J Clin Pharmacol (in press)Google Scholar
- 6.Catella F, Healy D, Lawson JA, FitzGerald GA (1986) Long-lived enzymatic metabolites of thromboxane A2: a quantitative index of thromboxane A2 formation in the human circulation. Proc Natl Acad Sci USA 83: 5861–5865Google Scholar
- 7.Lawson JA, Patrono C, Ciabattoni G, FitzGerald GA (1986) Long-lived enzymatic metabolites of thromboxane B2 in the human circulation. Anal Chem 155: 198–205Google Scholar
- 8.Westlund P, Granström E, Kumlin M, Nordström A (1986) Identification of 11-dehydro-TXB2 as a suitable parameter for monitoring thromboxane production in the human. Prostaglandins 31: 929–960Google Scholar
- 9.Takasaki W, Nakagawa A, Tanaka Y, Nakamura K, Shindo H, Hayashi Y, Yamamoto S (1991) Enzyme immunoassay of human plasma 11-dehydro-thromboxane B2. Thromb Res 63: 331–341Google Scholar
- 10.Salmon JA, Flower RJ (1982) Preparation and assay of prostacyclin synthase. Methods Enzymol 86: 91–99Google Scholar
- 11.Hayashi Y, Shono F, Yamamoto S, Takasaki W, Nakagawa A, Watanabe K, Yamashita K, Miyazaki H (1990) Immunoaffinity purification of 11-dehydrothromboxane B2 from human urine and plasma for quantitative analysis by radioimmunoassay. Anal Biochem 187: 151–159Google Scholar
- 12.Takasaki W, Nakagawa A, Shigeta A, Tanaka Y (1992) Enzymelinked immunosorbent assay of CS-518, a thromboxane synthetase inhibitor, in rabbit plasma and platelets. J Immunoassay 13: 495–508Google Scholar
- 13.Asai F, Ito T, Ushiyama S, Matsuda K, Oshima T (1991) In vitro antiplatelet profiles of the new thromboxane synthetase inhibitor sodium 2-(1-imidazolylmethyl)-4,5-dihydrobenzo[b]-thiophene-6-carboxylate. Arzneimittelforschung 41: 506–510Google Scholar
- 14.FitzGerald GA, Oates JA (1984) Selective and nonselective inhibition of thromboxane formation. Clin Pharmacol Ther 35: 633–640Google Scholar
- 15.Tyler HM, Saxton CAPD, Parry MJ (1981) Administration to man of UK-37, 248-01, a selective inhibitor of thromboxane synthetase. Lancet I: 629–632Google Scholar
- 16.Nakashima M, Uematsu T, Takiguchi Y, Mizuno A, Kanamaru M (1989) Phase I study of Y-20811, a new long-acting thromboxane synthetase inhibitor by oral administration. J Clin Pharmacol 29: 568–576Google Scholar
- 17.Iwata T, Mikashima H, Takamatsu R (1990) Correlation between pharmacokinetics and pharmacological effects of Y-20811, a new thromboxane synthetase inhibitor. J Pharm Sci 79: 295–300Google Scholar
- 18.Roth GJ, Stanford N, Majerus PW (1975) Acetylation of prostaglandin synthetase by aspirin. Proc Natl Acad Sci USa 72: 3073–3076Google Scholar
- 19.Patrono C, Ciabattoni G, Pugliese F, Pierucci A, Blair IA, FitzGerald GA (1986) Estimated rate of thromboxane secretion into the circulation of normal humans. J Clin Invest 77: 590–594Google Scholar
- 20.Katayama S, Inaba M, Maruno Y, Akabane S, Kawazu S, Ishii J, Sawada M (1988) Determination of urinary thromboxane B2 and its major metabolites, 2.3-dinor-TXB2 and 11-dehydro-TXB2. Igakunoayumi 147: 919–920 (in Japanese with English abstract)Google Scholar