PENETRATION OF MITOMYCIN-C IN HUMAN BLADDER

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 a nd maintained in the bladder for 60 to 120 min at which time the solut ion was drained. Within 10 to 60 min after draining the drug solution, the bladder vasculature was ligated, and the bladder was removed. Tis sues were sectioned serially in layers parallel to the urothelium and analyzed for MMC concentration. Of the 24 patients evaluated, 17 patie nts had a low final MMC concentration in urine (<66 mug/ml) or had the MMC solution drained more than 30 min before ligation of the blood ve ssels. Among these 17 patients, the concentration in the urothelium wa s measurable in only 4 patients, while the concentrations in deeper ti ssues were not measurable. In the remaining 7 patients where the urine concentration was > 120 mug/ml and where the vasculature was ligated within 30 min after the MMC solution was drained, the bladder wall con tained significant MMC concentrations. The drug penetration was studie d in the latter 7 patients, using sections of bladder wall that were g rossly normal and non-tumor bearing. Concentrations in the bladder wal l declined semilogarithmically with tissue depth from the urothelium t o the deep muscle and reached a plateau at about 2000 mum depth. The m edian MMC concentrations were 5.6 mug/g in the urothelium and lamina p ropria interface, 2.7 mug/g in the lamina propria, and 0.9 mug/g in th e muscularis. The distance over which the MMC concentration decreased by one-half was about 500 mum. The concentration ratio between the uri ne and urothelium/lamina propria interface was about 35-fold. The mean plasma concentrations were 0.003, 0.1, and 0.4% of the mean concentra tion in urine, urothelium, and the averaged bladder tissue concentrati ons, respectively. Paired superficial tumor and normal tissues were ob tained from 5 bladders. In 4 of 5 cases, the concentration in tumors w as higher than in normal tissues, while the reverse was seen in the re maining tumor. In one sessile bladder tumor a complete concentration-d epth profile could be obtained. While the concentrations in the tumor tissue were 2-3-fold higher than that in the adjacent normal tissue, t he rate of concentration declined with respect to tissue depth and hen ce the distance over which the MMC concentration decreased by one-half was similar in both tumors. These data established the pharmacokineti c advantage of intravesical therapy in patients where the tumor-bearin g bladder tissues receive at least 250-fold higher concentration than the systemic host tissues. The tissue concentration-depth profiles wer e analyzed by two kinetic models, i.e., the distributed model which co mbines a drug diffusion process and a drug removal process by the perf using blood, and the simple diffusion model which does not include dru g removal by tissue blood flow. The observed logarithmic decline of dr ug concentration with respect to tissue depth is consistent with the d istributed tissue pharmacokinetic model. The drug removal by the tissu e blood flow is further supported by the low drug concentration in tis sues of the 17 patients in which the MMC solution was removed 30 min b efore ligating the bladder vasculatures and by the data in rabbits sho wing that tissue concentrations in bladders with intact blood flow dec lined with a half-life of 4 min after removing the drug solution. Thes e data confirm the important role of blood flow in removing drug from the tissue. A comparison of the kinetics of MMC penetration in human b ladders 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: 4347-4 354, 1991) shows nearly identical kinetic parameters in the two specie s. The kinetic parameters and the distributed model can be used to pro ject the drug concentration at various tissue depths for a given urine concentration.