BLADDER TISSUE PHARMACOKINETICS OF INTRAVESICAL TAXOL

Our previous studies have suggested that the ineffectiveness of intrav esical mitomycin C or doxorubicin therapy against muscle-invading blad der cancer is in part because of the inability of these drugs to penet rate the urothelium (the urothelial drug concentration is <5% of the c oncentration in urine). The goal of the present study was to identify agents that are efficiently absorbed across the urothelium. To evaluat e the potential use of taxol in intravesical therapy for bladder cance r, we examined the bladder tissue and systemic plasma pharmacokinetics of intravesical taxol in dogs. Animals (similar to 8 kg body weight) were given an instillation of taxol at 500 mu g in 20 mi water. At 120 min postinstillation, the bladder was emptied and excised, and about 85% of the dose was recovered in the urine. The taxol concentration in the urothelium was about 50% of the concentration in the urine, the c oncentrations then declined logarithmically in the underlying capillar y-perfused tissues. The average tissue concentration (similar to 2 mu g/g) was two to three times the reported plasma concentration of 0.75 mu g/ml in patients following intravenous infusion of the >100-fold hi gher dose of 250 mg/m(2). The steady-state plasma concentration was <0 .02% of the average tissue concentration, and was <0.05% of the maxima lly tolerated plasma concentration in patients. The octanol,water part itioning coefficients of taxol, doxorubicin, and mitomycin were >99, 0 .52, and 0.41, which parallels the rank order of the partitioning acro ss urothelium, i.e. taxol (similar to 50%) much greater than doxorubic in approximate to mitomycin C (similar to 3%). In summary, the partiti oning of taxol across the urothelium was more favorable than the parti tioning of mitomycin C and doxorubicin, and the systemic concentration of taxol resulting from intravesical treatment was insignificant in s pite of the extensive absorption into the bladder. We conclude that in travesical delivery of taxol provides a significant bladder tissue tar geting advantage, and that taxol represents a viable candidate drug fo r intravesical bladder cancer therapy.