6-ketoprostaglandin-f1-alpha and fenflumizole

Anti-platelet effects of fenflumizole, a new cyclo-oxygenase inhibitor, were studied in man ex vivo. Fenflumizole was given to male volunteers at the oral doses of 25, 50 or 100 mg per day, each dose for a period of seven days. The formation of thromboxane B2 (TXB2) during whole blood clotting, platelet aggregation induced by arachidonic acid and ADP, the formation of TXB2 during aggregation as well as serum concentration of fenflumizole were measured repeatedly during drug administration and for a fortnight after drug discontinuation. TXB2 formation during whole blood clotting was decreased dose-dependently by fenflumizole. The degree of inhibition of TXB2 formation was proportional to fenflumizole concentration in serum within each individual. The lag phase of platelet aggregation induced by arachidonic acid was prolonged and the formation of TXB2 during aggregation decreased by fenflumizole. No total inhibition of either TXB2 synthesis or platelet aggregation was caused by the fenflumizole doses used. The results show that the degree of inhibition of platelet thromboxane forming capacity by repeated doses of fenflumizole is closely related to the concentration of the drug in blood. Platelet aggregation however is less sensitive to changes in fenflumizole levels and cannot be assessed solely on the basis of cyclo-oxygenase activity.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Oral; Adult; Anti-Inflammatory Agents, Non-Steroidal; Blood Platelets; Humans; Imidazoles; Male; Platelet Aggregation; Thromboxane B2

Fenflumizole is a substituted triaryl-imidazole with anti-inflammatory activity. Its disposition in man was studied after single intravenous and oral doses to 8 healthy male volunteers. Formation of the prostanoids thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (6-k-PGF1 alpha) in clotting blood was studied concomitantly. The pharmacokinetics after intravenous doses (0.1 mg/kg) could be fitted to a three compartment model and the half-lives (t 1/2) corresponding to the three phases were 2 min., 1 hour and 15 hours, respectively. The volume of distribution was 386 l and the plasma clearance 0.5 l per min. Oral doses (0.5 mg/kg) were rapidly absorbed (t 1/2 = 0.2 hr) and the following elimination from plasma had two phases with half-lives of 1 hour and 14 hours. Bioavailability was 50% due to a pronounced first-pass effect. The two metabolites mono- and didemethylfenflumizole were detected after both oral and intravenous doses and their maximum plasma concentrations occurred after 1-2 hours irrespective of the administration route. A concentration dependent depression of prostanoid formation was seen, the IC50 for TXB2 and 6-k-PGF1 alpha being 19 and 53 ng/ml respectively.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Oral; Adult; Anti-Inflammatory Agents; Biological Availability; Humans; Imidazoles; Injections, Intravenous; Kinetics; Male; Metabolic Clearance Rate; Prostaglandins; Thromboxane B2

Fenflumizole (2-(2,4-difluorophenyl)-4,5-bis(4-methoxyphenyl)imidazole), a new non-steroidal anti-inflammatory drug, was given to healthy subjects in single oral doses of 0.1, 1 and 2 mg/kg. The effect of the drug was followed for up to 8 h by repeated tests of arachidonic acid-induced platelet aggregation and was related to its concomitant plasma concentration. Fenflumizole reversibly inhibited platelet aggregation and the degree of inhibition was found to be linearly correlated with the log plasma concentration. There was depression of the formation of thromboxane B2 and 6-keto-prostaglandin F1 alpha (the stable metabolites of thromboxane A2 and prostacyclin) in clotted whole blood measured by radioimmunoassay after fenflumizole 1 mg/kg. This effect was directly related to the concentration of the drug in plasma, the maximum effect being reached at fenflumizole concentrations greater than 200 ng/ml. EC50-values for inhibition of the formation of thromboxane B2 and 6-keto-prostaglandin F1 alpha were approximately 20 and 40 ng/ml, respectively. The results suggest that orally administered fenflumizole is a potent inhibitor of platelet aggregation and prostanoid formation.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Anti-Inflammatory Agents; Arachidonic Acid; Arachidonic Acids; Humans; Imidazoles; Male; Platelet Aggregation; Thromboxane B2; Thromboxanes