Salicylate Kinetics In The Rat: Relationship To Antithrombotic Activity

Abstract

Recently we reported that acetylsalicylic acid (ASA) 100 mg/kg i.v. had no antithrombotic effect in a rat model of arterial thrombosis whereas 200 mg/kg i.v. had significant antithrombotic activity. The present study investigates salicylate kinetics at the non-protective level. Carotid arteries of urethane-anesthetized rats were injured electrically (1 mA, DC, for 1 min) and thrombogenesis measured by recording downstream temperature. Right and left side injuries were compared before and after ASA, 100 mg/kg i.v. Blood samples were collected at various times post injection and serum assayed for salicylate content by Trinder’s method. All salicylate levels are reported as mg/dL ± SEM. Control injuries produced a temperature fall of 1.4°C ± 0.08 (SEM) and post ASA injuries a fall of 1.8°C ± 0.17 (SEM) (P < .1 > .05). Serum salicylate was 20 mg ± 4.58 1 min post injection and the calculated lh was 40 min with decay following first order kinetics. The intraperitoneal injection of ASA 200 mg/kg produced a serum salicylate level of 8.1 ± 1.55 5 min post injection with a peak of 19 ± 2.03 30 min post injection. Both absorption and elimination followed first order kinetics with Th values of 10 and 44 min respectively. Urine collected 40 min post injection contained 9.4 ± 3.38 free salicylate which increased to about 40 following chemical digestion, indicating the presence of metabolites. The results indicate that serum salicylate levels < 20 do not offer antithrombotic protection in this model and that this level is achieved only briefly following ASA 100 mg/kg i.v. or 200 mg/kg i.p. The brief half-life of ASA in the rat has implications for the interpretation of data concerning the inhibition of prostacyclin synthesis by vessel wall. The wide variation in effective ASA doses reported for various animal models of thrombosis is probably a function of the nature of the model rather than of efficient prostacyclin synthesis.