The influence of selective thromboxane synthetase inhibition with a novel imidazole derivative, UK-38,485, on prostanoid formation in man.


UK-38,485, a novel imidazole derivative, was used in two clinical trials with healthy male subjects to study the influence of thromboxane synthetase inhibition on prostanoid formation. In an open pharmacokinetic study, UK-38,485 administered orally in doses of 10, 20, 40, 60, and 100 mg significantly reduced serum thromboxane (TXB2) concentrations. With lower doses (10 and 20 mg) peak inhibition of serum thromboxane occurred 2 hr after dosing, with a mean percentage inhibition of 78% and 91%, respectively. For the higher doses (40, 60, and 100 mg) peak inhibition exceeded 99% 1 hr after dosing. After 8 hr the inhibition was dose related, ranging between 59% and 75%, and after 24 hr between 0 and 35%. In a second multiple-dose, double-blind, placebo-controlled, cross-over study, 50 mg UK-38,485 given twice daily for 1 week selectively inhibited thromboxane synthetase. The excretion of 2,3-dinor-TXB2, the major urinary metabolite of endogenously formed thromboxane, was significantly reduced, whereas the urinary excretion of 2,3-dinor-6-keto-PGF,a, the main metabolite of endogenous prostacyclin, and the plasma concentrations of 6-keto-PGF,a showed no significant increases compared with levels in the placebo period. In platelet suspensions stimulated ex vivo with arachidonic acid and in serum of incubated whole blood, TXB2 concentrations were reduced and a significant redirection of endoperoxide metabolism to antiaggregatory and vasodilatory prostaglandins '2, E2, and D2 was demonstrated after the influence of UK-38,485. Platelet lipoxygenase metabolites were not measurably altered. The drug was well tolerated. In both studies, no clinically relevant changes in laboratory safety and hemodynamic parameters, bleeding, or clotting time were observed. From the time course of the plasma drug concentrations, the inhibition of thromboxane synthesis, and the redirection of endoperoxide metabolism it can be concluded that UK-38,485 is rapidly absorbed and has a long-lasting effect on prostanoid formation. Circulation 68, No. 4, 821-826, 1983. THROMBOXANE A2 (TXA2) and prostaglandin (PG) 12 exert opposite effects on platelet aggregation and vascular resistance, and the balance between these compounds has been proposed to be one of the factors that determine platelet reactivity, endothelial thromboresistance, and vascular tone.' Increased thromboxane formation has been found to be associated with various conditions such as vasospasm and platelet aggregation in coronary heart disease,>' vasoconstriction in hydronephrotic kidneys, incipient renal graft rejection,6 severe septic shock associated with acute respiratory distress syndrome,7 pulmonary embolism,8 and allergenic bronchospasm.9 Selective inhibition of thromboxane synthesis and the redirection of endoperFrom Medizinische Klinik Innenstadt der Universitat Miinchen and Pfizer Clinical Research, Muinchen, F.R.G. Supported in part by Deutsche Forschungsgemeinschaft, We 681. Address for correspondence: Peter C. Weber, M.D., Medizinische Klinik Innenstadt der Universitat, Ziemssenstrasse 1, 8000 Miinchen 2, F.R.G. Received March 29, 1983; revision accepted June 9, 1983. Vol. 68, No. 4, October 1983 oxide metabolism toward PGI2, PGE2, and PGD2 will possibly offer a new therapeutic approach to those disease states in which increased thromboxane formation is critically involved. Ex vivo and in vitro studies with thromboxane synthesis inhibitors5' 1012 have demonstrated that these compounds selectively inhibited thromboxane formation and partially redirected endoperoxide metabolism.'3' 14 However, almost no data are available to determine whether thromboxane synthetase inhibition also redirects endoperoxide metabolism under basal in vivo conditions in man. This study reports on the pharmacokinetics and the biochemical effects ex vivo and in vivo of a novel imidazole derivative, UK-38,485, '5 in healthy male subjects. The potency and specificity of action of this drug were examined by measuring formation of TXB2 and other cyclooxygenase products in serum after incubation of whole blood, by monitoring cyclooxygenase and lipoxygenase products in platelet suspensions after 821 by gest on N ovem er 6, 2017 D ow nladed from


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@article{Fischer1983TheIO, title={The influence of selective thromboxane synthetase inhibition with a novel imidazole derivative, UK-38,485, on prostanoid formation in man.}, author={S Fischer and M. Struppler and B Boehlig and C. Bernutz and W . Wober and P C Weber}, journal={Circulation}, year={1983}, volume={68 4}, pages={821-6} }