Electromotive versus passive diffusion of mitomycin C into human bladder wall: Concentration-depth profiles studies

The objectives of these investigations were: (a) to make a preliminary stud y to assess concentration-depth profiles of mitomycin C (MMC) in the bladde r wall at specified time intervals after passive diffusion (PD); and (b) to conduct a major study to compare concentration-depth profiles after PD and electromotive drug administration (EMDA) of MMC. Full thickness sections o f viable human bladder wall were placed in two-chamber cells with urotheliu m exposed to donor compartments containing 40 mg of MMC in 100 ml of 0.96% NaCl solutions and with serosa-facing receptor compartments containing 0.9% NaCl solutions. In the preliminary study during each of nine experimental sessions, five sections of bladder wall were individually exposed to MMC fo r either 5, 15, 30, 45, or 60 min. In the major study, an anode and a catho de were sited in the donor and receptor compartments, and 14 paired experim ents-current (20 mA)/no current-were conducted over a 30-min period. Bladde r wall sections were cut serially into 40-mu m slices parallel to the uroth elium and analyzed by high-performance liquid chromatography for MMC concen tration (mu g/g wet tissue weight). Tissue viability and morphology and MMC stability were assessed by trypan-blue exclusion test, histological examin ation, and mass spectrometry analysis. In the preliminary study (PD only), mean MMC concentrations (mu g) at 5, 15, 30, 45, and 60 min were: (a) for u rothelium, 15.3, 60.0, 58.2, 60.1, and 57.8, respectively; (6) for lamina p ropria, 2.2, 18.9, 19.3, 16.1, and 17.3, respectively; and (c) for muscular is, 0.4, 2.0, 1.8, 1.3, and 2.4, respectively. In the comparative study, MM C concentrations and coefficients of variation (CV) were as follows: (a) fo r urothelium after PD, 46.6 with CV = 69%, and after EMDA, 170.0 with CV = 43% (P < 0.0001); (6) for lamina propria after PD, 16.1, with CV = 60%, and after EMDA, 65.6 with CV = 29% (P < 0.0001); and (c) for muscularis after PD, 1.9 with CV = 82%, and after EMDA, 15.9 with CV = 82% (P < 0.0005). All of the bladder sections remained viable, and the chemical structure of MMC was unchanged. It was concluded that EMDA significantly enhances MMC trans port into all of the layers of the bladder wall, and sections of viable hum an bladder are a reliable tool for assessing different modes of drug delive ry.