The hypothesis that weakly acidic drugs are reabsorbed from the urinary bladder was tested using adult female Fischer rats. Bladder reabsorption would have direct implications for pharmacokinetic data analysis of compounds with significant renal excretion. Sodium salicylate (SA) undergoes extensive renal excretion in the rat, and was selected as the model compound. Methodology was developed to administer an intravesical dose to a rat via a transurethral catheter. The barrier function and the integrity of the bladder urothelium were examined by light and electron microscopy, and by monitoring leakage of [14C] inulin (MW 5000) and fluorescein (MW 376). Using these methodologies, we found that urothelial integrity was maintained in about 80% of the animals. Animals that showed tissue damage were excluded from the study. In the pharmacokinetic experiments, one group of animals received an i.v. dose of SA (1.5 or 3 mg/kg), the second group received an intravesical dose of 30 mg/kg (approximately 0.3 ml) and the third group received concomitantly an i.v. tracer dose of [14C] SA and an intravesical dose of unlabeled SA (30 mg/kg). The intravesical dose was removed after 90 min. The intravesical administration of SA produced maximal blood concentrations of 10.8 +/- 5.6 micrograms/ml (mean +/- S.D., n = 10) at 90 to 100 min. The fraction of the intravesical dose recovered after 90 min was between 45 and 75%, which indicates an upper limit of 25 to 55% loss by processes including absorption. The bioavailability of the intravesical dose, calculated from the blood data and the clearance of the i.v. doses, was between 4 and 23% and averaged about 13%.(ABSTRACT TRUNCATED AT 250 WORDS)