Bladder tissue uptake of mitomycin C during intravesical therapy is linear with drug concentration in urine

The design of an ongoing Phase III study of intravesical mitomycin C therapy to treat bladder cancer is partly based on the assumption that drug penetration into bladder tissue is linearly related to drug concentration. The present study was designed to (a) test this assumption and (b) to compare drug concentrations in tumor and adjacent normal tissues in human bladders. We previously reported the uptake kinetics of a 20-mg dose in dog and human bladders (M. G. Wientjes et al., Cancer Res., 51: 4347-4354, 1991, and Cancer Res., 53: 3314-3320, 1993). The present study used a 40 mg/20 ml dose. Serial blood and urine samples were taken from dogs during the 120-min instillation. Bladder tissues were harvested from dogs and patients at the end of instillation. A comparison of the results of the present and previous studies indicates identical tissue penetration kinetic parameters in dogs for the two doses, i.e., a approximately 30-fold concentration drop across the urothelium and a half-width of approximately 500 microns. In addition, the average tissue concentration in dog and human bladders attained with the 40-mg dose (8.77 micrograms/g in dogs and 7.55 micrograms/g in humans) was about twice that achieved with the 20-mg dose (4.33 micrograms/g in dogs and 3.91 micrograms/g in humans). In dogs, the plasma concentration of MMC reached a steady state within 10 min; the mean maximal plasma concentration was 8.5 ng/ml. This plasma concentration is indistinguishable from the concentration derived from the 20-mg dose and indicates a minimal systemic exposure even at the higher dose. The average MMC concentration in tumor-bearing tissues was about 40% higher than the concentration in adjacent normal tissues (P = 0.01). In conclusion, the linear relationship between drug uptake in bladder tissues and drug concentration in urine supports the assumption used in the design of the ongoing Phase III clinical trial.