Salicylate Accumulating During Repeated Aspirin Administration Prevents The Inhibitory Effect Of Aspirin On Vascular Prostacyclin

In vitro studies have shown that salicylate (SA) effectively protects cyclooxygenase from aspirin (ASA) inhibition. The purpose of this study was to investigate in vivo this pharmacological interaction and to evaluate the possibility that SA accumulating during repeated ASA treatment interferes with the inhibitory effect of the unchanged drug on vascular prostacyclin(PGI₂). Male CD-COBS rats were given i.v. saline or SA (25-100 mg/kg) followed after 15 min by ASA (2.5-10 mg/kg). The animals were killed 30 min after the last treatment. PGI₂ activity was bioassayed on thoracic aorta rings and confirmed by RIA of 6-Keto-PGF_1α. Blood SA levels were measured by fluorimetric assay. SA pretreatment showed dose-related competitive prevention of the inhibitory effect of ASA on vascular PGI₂ which was almost complete at a dose ratio of 5:1. Further experiments were performed with single or repeated doses of ASA (200 mg/kg). This resulted in different blood SA levels after 24 hours when in all conditions vascular PGI₂ recovered by more than 50% of basal value. At that moment further inhibition (60-90%) of PGI₂ by a test dose of ASA (10 mg/kg) could only be obtained if blood SA levels were lower than 100 μg/ml. Above this level an inverse linear correlation (r = 0.87, p< 0.01) was found between blood SA levels and the inhibitory activity of ASA. In particular, almost no ASA activity could be detected at blood SA levels around 250 μg/ml.

These results show that SA and ASA interact in vivo at vascular levels. This interaction could have clinical implications in view of the rapid hydrolysis of ASA to SA and slow elimination of SA from blood. These observations add a new piece of information to the current debate on the optimal ASA treatment schedule for thrombosis prevention.