BLADDER TISSUE PHARMACOKINETICS AND ANTITUMOR EFFECT OF INTRAVESICAL 5-FLUOROURIDINE

The present study evaluates whether intravesical 5-fluorouridine (FUR) , a potent fluorinated pyrimidine, is effective against bladder cancer , The tissue and plasma pharmacokinetics of i.v. and intravesical FUR were studied in dogs to determine the tissue targeting advantage by th e intravesical route, The i.v. study used a bolus FUR dose of 4 mg/kg, which is tolerated in humans, The disposition of FUR was biphasic, wi th a peak concentration of 8.8 mu g/ml and a clearance of 127 ml/min/k g. 5-Fluorouracil was the major circulating metabolite, reaching a pea k concentration of 3.2 mu g/ml. In the intravesical study, FUR (simila r to 2 mg/kg in 20 ml of water) was instilled in the dog bladder, At t he end of the 2-h treatment, FUR concentration in urine decreased by a bout 40%, due mainly to dilution by residual and newly produced urine, The concentration at the interface between urothelium and lamina prop ria was 14 mu g/g, or similar to 2% of the urine concentration, and de clined logarithmically to 2 mu g/g in the deep muscles, The concentrat ions of FUR and 5-fluorouracil in plasma were below the assay detectio n limit of 20 ng/ml, or >200-fold lower than the concentration after t he i.v. dose (adjusted to the difference in the i.v. and intravesical dose), These data indicate a >200-fold advantage in the reduction of s ystemic exposure by the intravesical route, To determine whether the a chievable tissue concentrations of FUR produced significant antitumor activity, we studied the effect of FUR against human bladder tumors ma intained as 3-dimensional histocultures. The FUR concentrations (IC(50 )s) required to produce 50% inhibition of DNA precursor ([H-3]thymidin e or bromodeoxyuridine) incorporation in human superficial bladder tum ors (i.e., T-a and T-1 tumors, n = 4) and muscle-invading tumors (i.e. , T-3 and T-4 tumors, n = 4) were 9 and 22 mu g/ml, respectively, In c onclusion, intravesical FUR therapy delivers effective drug concentrat ion to superficial bladder tissues without resulting in appreciable sy stemic blood concentration, We propose that intravesical FUR represent s a potentially effective treatment against superficial bladder cancer .