Penetration of Mitomycin C in Human Bladder

Abstract

The penetration of mitomycin C (MMC) in bladder tissue was studied in patients who received intravesical chemotherapy at the time of radical cystectomy. An intravesical dose of MMC (20 mg/40 ml) was instilled and maintained in the bladder for 60 to 120 min at which time the solution was drained. Within 10 to 60 min after draining the drug solution, the bladder vasculature was ligated, and the bladder was removed. Tissues were sectioned serially in layers parallel to the urothelium and analyzed for MMC concentration. Of the 24 patients evaluated, 17 patients had a low final MMC concentration in urine (<66 µg/ml) or had the MMC solution drained more than 30 min before ligation of the blood vessels. Among these 17 patients, the concentration in the urothelium was measurable in only 4 patients, while the concentrations in deeper tissues were not measurable. In the remaining 7 patients where the urine concentration was > 120 µg/ml and where the vasculature was ligated within 30 min after the MMC solution was drained, the bladder wall contained significant MMC concentrations. The drug penetration was studied in the latter 7 patients, using sections of bladder wall that were grossly normal and non-tumor bearing. Concentrations in the bladder wall declined semilogarithmically with tissue depth from the urothelium to the deep muscle and reached a plateau at about 2000 µm depth. The median MMC concentrations were 5.6 µg/g in the urothelium and lamina propria interface, 2.7 µg/g in the lamina propria, and 0.9 µg/g in the muscularis. The distance over which the MMC concentration decreased by one-half was about 500 µm. The concentration ratio between the urine and urothelium/lamina propria interface was about 35-fold. The mean plasma concentrations were 0.003, 0.1, and 0.4% of the mean concentration in urine, urothelium, and the averaged bladder tissue concentrations, respectively. Paired superficial tumor and normal tissues were obtained from 5 bladders. In 4 of 5 cases, the concentration in tumors was higher than in normal tissues, while the reverse was seen in the remaining tumor. In one sessile bladder tumor a complete concentration-depth profile could be obtained. While the concentrations in the tumor tissue were 2–3-fold higher than that in the adjacent normal tissue, the rate of concentration declined with respect to tissue depth and hence the distance over which the MMC concentration decreased by one-half was similar in both tumors. These data established the pharmacokinetic advantage of intravesical therapy in patients where the tumor-bearing bladder tissues receive at least 250-fold higher concentration than the systemic host tissues.

The tissue concentration-depth profiles were analyzed by two kinetic models, i.e., the distributed model which combines a drug diffusion process and a drug removal process by the perfusing blood, and the simple diffusion model which does not include drug removal by tissue blood flow. The observed logarithmic decline of drug concentration with respect to tissue depth is consistent with the distributed tissue pharmacokinetic model. The drug removal by the tissue blood flow is further supported by the low drug concentration in tissues of the 17 patients in which the MMC solution was removed 30 min before ligating the bladder vasculatures and by the data in rabbits showing that tissue concentrations in bladders with intact blood flow declined with a half-life of 4 min after removing the drug solution. These data confirm the important role of blood flow in removing drug from the tissue. A comparison of the kinetics of MMC penetration in human bladders with the previous data in dogs (M. G. Wientjes, J. T. Dalton, R. A. Badalament, J. R. Drago, and J. L-S. Au, Cancer Res., 51: 4347–4354, 1991) shows nearly identical kinetic parameters in the two species. The kinetic parameters and the distributed model can be used to project the drug concentration at various tissue depths for a given urine concentration.