Abstract
The pharmacokinetics and pharmacodynamics of rolafagrel (FCE 22178), a novel thromboxane synthase inhibitor, were evaluated after single and multiple oral doses in eight healthy volunteers.
After a single dose (400 mg), the drug was absorbed rapidly, peak plasma concentrations being attained within 2 h in all subjects. Elimination followed a biphasic course, with a rapid initial decline followed after 12–24 h by a late phase with a terminal half-life of about 10h. About 100% of the administered dose could be recovered in urine within 72 h, mostly in conjugated form. During multiple dosing (400 mg t.i.d. for 5 days), steady-state conditions were approached on day 2 and AUC values over a dosing interval were similar to those observed after a single dose (72.3 vs 76.3 μg·ml−1·h). Pharmacokinetic parameters calculated after multiple doses were similar to those observed after a single dose (Cmax: 20.1 vs 18.2 μg·ml−1; tmax: 1.2 vs 1.1 h; terminal half-life: 10.9 vs 11.4 h; CL: 85.2 vs 70.4 ml·h−1;V: 1.23 vs 1.241·kg−1).
Platelet generation of thromboxane B2, the stable breakdown product of thromboxane A2, was inhibited by 85% at a plasma rolafagrel concentration of about 4μg·ml−1, and only a small increase in inhibition was observed at higher concentrations.
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References
Alessandrini P, Salvati P, Pugliese F, Ciabattoni G, Patrono C (1990) Inhibition by FCE 22178 of platelet and glomerular thromboxane synthase in animal and human kidney disease. Adv Prostaglandin Thromboxane Leukotriene Res 21:707–710
Oates JA, FitzGerald GA, Branch RA, Jackson EI, Knapp HR, Roberts LJ II (1988) Clinical implications of prostaglandin and thromboxane A2 formation. N Engl J Med 319:761–767
Salvati P, Ferti C, Ferrario RG, Lamberti E, Buzzi L, Bianchi G, Remuzzi G, Perico N, Benigni A, Braidotti P, Coggi G, Pugliese F, Patrono C (1990) Role of enhanced glomerular synthesis of thromboxane A2 in progressive kidney disease. Kidney Int 38:447–458
Patrono C, Pierucci A (1990) The use of antiplatelet agents in glomerulonephritis: a pharmacological approach. Nephrol Dial Transplant 5 [Suppl 1]:29–32
Zoja C, Perico N, Remuzzi G (1991) Antiplatelet agents: effects on the progressive renal disease. Am J Kidney Dis 17 [Suppl 1]:98–102
Zoja C, Perico N, Corna D, Benigni A, Gabanelli M, Morigi M, Bertani T, Remuzzi G (1990). Thromboxane synthesis inhibition increases renal prostacyclin and prevents renal disease progression in rats with remnant kidney. J Am Soc Nephrol 1:799–807
Ferti C, Pierucci L, Corsi G, Salvati P, Ferrario R (1987) A new TxA2 synthetase inhibitor reduces adriamycin-induced nephrotoxic syndrome in rats (abstract). International Symposium on Renal Eicosanoids, Capri, 9–11 June, p 23
Salvati P, Lamberti E, Ferrario RG, Pugliese F, Patrono C (1992) Long-term thromboxane-synthase inhibition improves survival in murine lupus nephritis (abstract). XXV Annual Meeting of the American Society of Nephrology, Washington, 15–18 November
Macconi D, Benigni A, Morigi M, Ubiali A, Orisio S, Livio M, Perico N, Bertani T, Remuzzi C, Patrono C (1989) Enhanced glomerular thromboxane A2 mediates some pathophysiologic effect of platelet-activating factor in rabbit nephrotoxic nephritis: evidence from biochemical measurements and inhibitor trials. J Lab Clin Med 113:549–560
Ferti C, Pierucci L, Corsi G, Ferrario R, Mariotto T, Salvati P, Cozzi P (1987) Effect of FCE 22178, a new TxA2 synthetase inhibitor, on platelet aggregation and TxA2 production in rabbit (abstract). XI Congress on Hemostasis, Brussels, 4–11 July
Strolin-Benedetti M, Santarato D, Pianezzola E, Jannuzzo MG, Ferti C, Cusi D (1989) Pharmacokinetics of FCE 22178, a new thromboxane synthase inhibitor, in healthy volunteers and relationship with thromboxane B2 (TxB2) production. Eur J Clin Pharmacol 36 [Suppl]: A185
Barrow SE, Kontessis PS, Jones SL, Alessandrini P, De Cosmo S, Ritter JM, Viberti GC (1991) Effects of selective inhibition of thromboxane biosynthesis on renal function in insulin-dependent diabetic patients with nephropathy. Br J Clin Pharmacol 33:562–563P
Ciabattoni G, Alessandrini P, Pugliese F, Gambardella S, Gatta R, Frontoni S, Patrono C (1990) Time- and dose-dependence of inhibition of thromboxane biosynthesis by the selective thromboxane-synthase inhibitor FCE 22178 in diabetic patients. Eur J Pharmacol 183:2079
Kontessis PS, Jones SL, Barrow SE, Stratton PD, Alessandrini P, De Cosmo S, Ritter JM, Viberti GC (1993) Effect of selective inhibition of thromboxane synthesis on renal function in diabetic nephropathy. J Lab Clin Med 121:415–423
Remuzzi G, Santarato D, Benigni A, Alessandrini P, Patrono C (1989) Platelet and urinary thromboxane B2 inhibition by a new orally active thromboxane synthase inhibitor in patients with lupus nephritis (abstract). II International Conference on Systemic Lupus Erythematosus, Singapore, 26–30 November
Bertin D, Pianezzola E, Strolin Benedetti M, Roncucci R (1990) Pharmacokinetic profile and metabolic pattern of FCE 22178, a new inhibitor of thromboxane synthase, in animals and humans (abstract). Convegno Nazionale di Farmacocinetica: Aspetti Teorici e Pratici, Siena, 27–30 May, no. 73
Bertin D, Strolin Benedetti M, Alessandrini P, Santarato D, Patrignani P, Barzaghi N, Perucca E (1990) Pharmacokinetics of FCE 22178 during multiple-dose regimen in healthy volunteers and relationship with thromboxane B2 production. Eur J Pharmacol 183:1852
Li RC, Narang PK, Lewis RC, Hatfield NZ, Rossi DT, Colborn DC (1993) A phase I dose-ranging safety and pharmacokinetics study of a novel oral thromboxane synthase inhibitor, FCE 22178. J Clin Pharmacol 33:373–380
Pianezzola E, Stocco S, Moro E (1986) HPLC method for the determination of FCE 22178 in plasma. Farmitalia-Carlo Erba, Internal Report FCE 22178/112i
Patrono C, Ciabattoni G, Pinca E, Pugliese F, Castrucci G, De Salvo A, Satta MA, Peskar BA (1980) Low dose aspirin and inhibition of thromboxane B2 production in healthy subjects. Thromb Res 17:317–327
Patrono C, Ciabattoni G, Remuzzi G, Gotti E, Bombardieri S, Di Munno O, Tartarelli G, Ginotti GA, Simonetti BM, Pierucci A (1985) Functional significance of renal prostacyclin and thromboxane A2 production in patients with systemic lupus nephritis. J Clin Invest 76:1011–1018
Holford NHG, Sheiner LB (1981) Understanding the dose effect relationship: clinical application of the pharmacokinetic-pharmacodynamic models. Clin Pharmacokinet 6:429–453
Wilkinson GR, Shand DG (1975) A physiological approach to hepatic drug clearance. Clin Pharmacol Ther 18:377–390
Thomassin J, Battaglia R, Allievi C, Castelli MG, Strolin Benedetti M (1993) In vivo glucuronidation in rat and humans of 5,6-dihydro-7-(1H-imidazol-1-yl)-naphtalene-2-carboxylic acid, a selective inhibitor of thromboxane synthase. Drug Metab Dispos 21:151–155
Battaglia R, Castelli MG, Salgarollo G, Pianezzola E, Cocchiara G, Strolin Benedetti M (1990) Excretion balance and urinary metabolism of3H-FCE 22178 in rat, dog and man (abstract). XII European Workshop on Drug Metabolism, Basel, 16–21 September, p 130
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Gatti, G., Bartoli, A., Perucca, E. et al. Pharmacokinetic and pharmacodynamic studies following single and multiple doses of rolafagrel, a novel inhibitor of thromboxane synthase, in normal volunteers. Eur J Clin Pharmacol 47, 275–280 (1994). https://doi.org/10.1007/BF02570508
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DOI: https://doi.org/10.1007/BF02570508