Rats are frequently used as an animal model for studies of the antithrombotic action of aspirin. The purpose of this investigation was to explore factors that influence the systemic exposure to unhydrolyzed aspirin after oral and systemic administration of the drug to adult male Sprague-Dawley rats. The experiments were performed according to a crossover design, and drug concentration measurements were made on whole blood. Intravenous injection and oral administration of aspirin (200 mg/kg) showed that the drug is eliminated rapidly (total clearance approximately 45 ml/min/kg; half-life approximately 8 min), that only about one-fourth of the dose is absorbed intact, and that the systemic availability of the oral dose is highly variable (coefficient of variation approximately 60%). A 40 mg/kg i.v. dose was cleared almost twice as rapidly as a 200 mg/kg i.v. dose. Injection of salicylic acid to yield concentrations similar to those obtained after injection of the large dose of aspirin (approximately 400 mg/l) reduced the total clearance of a 40 mg/kg i.v. dose of aspirin by about one-third, suggesting product inhibition of ester hydrolysis. The systemic availability of aspirin infused into the portal circulation was about 80% over a wide range of infusion rates, showing that presystemic hydrolysis of the drug occurs mainly in the gut. As in humans, absorption of orally administered aspirin affects the exponential decline of aspirin concentrations in blood, resulting in an apparent half-life substantially longer than the actual biologic half-life of the drug after i.v. injection.(ABSTRACT TRUNCATED AT 250 WORDS)