Summary
The pharmacokinetics and pharmacodynamic effect on platelet activation of a single 800 mg oral dose of BM 13.177 have been investigated in 8 male volunteers. BM 13.177 disappeared from plasma with a terminal elimination half-life of 0.85 h. 52% of the dose was excreted unchanged in urine. Assuming complete absorption, total clearance was calculated to be 741.3 ml/min and renal celearance to range from 310.4 to 396.9 ml/min. The pharmacodynamic studies were performed ex vivo/in vitro in platelets stimulated either with methyl mercury chloride or with U 46619. Methyl mercury chloride is a platelet activator that requires TXA2 formation from endogenous arachidonic acid, whereas U 46619 is a stable PGH2 analogue and thromboxane mimetic at the platelet TXA2/PGH2 receptor. A close correlation between the plasma concentration-time profile of BM 13.177 and inhibition of platelet shape change or aggregation was demonstrated.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Best LC, Holland TK, Jones PBB, Russel RGG (1980) The interrelationship between thromboxane biosynthesis, aggregation and 5-hydroxytryptamine secretion in human platelets in vitro. Thromb Haemost 43: 38–40
Coleman RA, Humphrey PPA, Kennedy I, Levy GP, Lumley P (1980) U 46619 — a selective thromboxane A2-like agonist? Br J Pharmacol 68: 127 P
Gresele P, Deckmyn H, Arnout J, Lemmens J, Janssens W, Vermylen J (1984) BM 13.177, a selective blocker of platelet and vessel wall thromboxane receptors, is effective in man. Lancet 1: 991–994
Jones RL, Smith GM, Wilson NH (1984) The effect of a synthetic prostanoid EP 092 on intravascular platelet aggregation and bronchoconstriction. Br J Pharmacol 81 [Suppl]: 100 P
Koch-Weser J, Greenblatt DJ, Sellers EM, Shader RI (1982) Drug disposition in old age. N Engl J Med 306: 1081–1086
Macfarlane DE (1981) The effects of methyl mercury on platelets. Mol Pharmacol 19: 470–476
Mehta P, Mehta J, Pepine CJ (1979) Platelet aggregation across the myocardial vascular bed in man: Normal versus diseased coronary arteries. Thromb Res 14: 423–432
Patscheke H (1979) Correlation of activation and aggregation of platelets. Discrimination between anti-activating and antiaggregating agents. Haemostasis 8: 65–81
Patscheke H (1984) Thromboxane synthetase inhibition potentiates washed platelet activation by endogenous and exogenous arachidonic acid. Biochem Pharmacol 34: 1151–1156
Patscheke H and Stegmeier K (1984a) Investigations on a selective non-prostanoic thromboxane antagonist, BM 13,177, in human platelets. Thromb Res 33: 277–288
Patscheke H and Stegmeier K (1985) Effects of the prostaglandin H2/thromboxane A2 antagonist BM 13.177 on human platelets. In: Advances in prostaglandin, thromboxane and leukotriene research, vol. 13. Raven Press, New York 371–373
Patscheke H, Stegmeier K, Müller-Beckmann B, Sponer G, Staiger C, Neugebauer G (1984a) Inhibitory effects of the selective thromboxane receptor antagonist BM 13.177 on platelet aggregation, vasoconstriction and sudden death. Biomed Biochem Acta 43: S312-S318
Patscheke H, Dubler D, Deranleau D, Lüscher EF (1984b) Optical shape change analysis in stirred and unstirred human platelet suspensions. A comparison of aggregometric and stopped-flow turbidimetric measurements. Thromb Res 33: 341–353
Rowland M, Tozer TN (1980) Clinical pharmacokinetics. Concepts and applications. Lea & Febiger, Philadelphia 291–293
Stegmeier K, Pill J, Müller-Beckmann B, Schmidt FH, Witte C, Wolff HP, Patscheke H (1984) The pharmacological profile of the thromboxane A2-antagonist BM 13.177. A new antiplatelet and anti-thrombotic drug. Thromb Res 35: 379–395
Vane JR (1971) Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature (New Biol) 231: 232–235
Vermylen J, Carreras LO, Schaeren JV, DeFreyn G, Machin SJ, Verstraete M (1981) Thromboxane synthetase inhibition as anti-thrombotic strategy. Lancet 1: 1073–1075
Weiner IM, Mudge GH (1964) Renal tubular mechanism for excretion of organic acids and bases. AM J Med 36: 743–762
Wise WC, Cook JA, Halushka PV, Knapp DR (1980) Protective effects of thromboxane synthetase inhibitors in rats in endotoxic shock. Circ Res 46: 854–859
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Staiger, C., Patscheke, H., Neugebauer, G. et al. Single dose pharmacokinetics and effects on platelet function of the thromboxane receptor blocker BM 13.177. Eur J Clin Pharmacol 29, 573–579 (1986). https://doi.org/10.1007/BF00635895
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00635895