TISSUE PHARMACOKINETICS OF MITOMYCIN-C IN THE HUMAN BLADDER WALL AFTER PASSIVE DIFFUSION, THERMO-CHEMOTHERAPY AND ELECTROMOTIVE DRUG ADMINISTRATION

Background and Aim: Device-assisted intravesical mitomycin-C (MMC), including electromotive drug administration (EMDA) and thermo-chemotherapy (TC), shows promise and offers the prospect for greater efficacy than passive diffusion (PD). Integration of drug delivery with tissue pharmacodynamic data provides a means for the rational design of intravesical treatments. The objective of this study was to compare concentration-depth profiles of MMC in the bladder wall after PD, TC and EMDA. Materials and Methods: During each experiment, three full-thickness sections of viable human bladder wall were placed between the two chambers of individual diffusion cells, with urothelium exposed to donor compartments containing 40 mg of MMC in 100 ml water and with serosa-facing receptor compartments containing 100 ml of 0.9% NaCl solutions. Fifteen paired experiments were conducted over a 30-min period. In TC experiments, the two chamber cells were placed in an incubator at 45C, with the donor compartments filled with heated MMC solutions at 44C. In EMDA experiments, an anode was placed in the donor compartment and a cathode in the receptor compartment. The electrodes were connected to the current generator and experiments were performed with pulsed direct current of 23 mA. No electric current or hyperthermia were applied in PD control experiments. Bladder wall sections were cut serially into 40-mm slices parallel to the urothelium, the tissues were homogenized and supernatants analyzed by high-performance liquid chromatography for MMC concentration. Results: Concentration-depth profiles of MMC in bladder wall tissues following PD, TC and EMDA are reported below. Data are expressed as the mean c standard error of the mean (SEM) of 15 replicates per experimental group (kg of MMC/g of wet tissue). The mean concentration of MMC transported in urothelium, lamina propria and muscle layers by EMDA significantly exceeded that achieved by PD and TC. Non significant differences were found between PD and TC. Conclusion: EMDA significantly enhances MMC transport into all of the layers of the bladder wall compared to both PD and TC.