OBJECTIVES: To assess in a phase II pharmacokinetic study whether different pH levels, dilution volumes and exposure times affect intracellular bioavailability and systemic absorption of gemcitabine. SUBJECTS AND METHODS: Six arms of three patients each with a non-muscle-invasive bladder cancer (NMIBC) were planned to receive six combinations of two different dilution volumes (50 mL vs 100 mL), two pH levels (2.5-3.5 vs 5.5) and two exposure times (1 h vs 2 h) of the study drug. Blood samples were taken before, during and 1 h after drug instillation. Cold biopsy specimens from the exophytic tumor, its base of implant and a macroscopically healthy mucosa were taken during transurethral resection. High-pressure liquid chromatography/high-resolution mass spectrometry (HPLC/HRMSn) analysis of plasma and tissue samples was used to determine concentrations of gemcitabine (dFdC) and its inactive metabolite (dFdU). RESULTS: The arm at pH 5.5 in 50 mL was withdrawn as 2000 mg dFdC are insoluble in these conditions. The different instillation conditions resulted in negligible plasma dFdC concentrations but significant differences in intracellular content and metabolism of dFdC. The lowest intratissue concentration of dFdC was detected in a 50 mL solution at a pH of 2.5-3.5 kept in the bladder for 1 h (standard arm). A pH 5.5 solution in 100 mL with a 2-h exposure favored the maximal intratumoral dFdC absorption which was 90 times higher than that recorded in the standard arm. CONCLUSIONS: The most commonly reported administration scheme of gemcitabine produced the lowest tissue bioavailability of dFdC. Other combinations of pH, dilution volume and duration of instillation proved more advantageous and merit testing in clinical trials.
OBJECTIVES: To assess in a phase II pharmacokinetic study whether different pH levels, dilution volumes and exposure times affect intracellular bioavailability and systemic absorption of gemcitabine. SUBJECTS AND METHODS: Six arms of three patients each with a non-muscle-invasive bladder cancer (NMIBC) were planned to receive six combinations of two different dilution volumes (50 mL vs 100 mL), two pH levels (2.5-3.5 vs 5.5) and two exposure times (1 h vs 2 h) of the study drug. Blood samples were taken before, during and 1 h after drug instillation. Cold biopsy specimens from the exophytic tumor, its base of implant and a macroscopically healthy mucosa were taken during transurethral resection. High-pressure liquid chromatography/high-resolution mass spectrometry (HPLC/HRMSn) analysis of plasma and tissue samples was used to determine concentrations of gemcitabine (dFdC) and its inactive metabolite (dFdU). RESULTS: The arm at pH 5.5 in 50 mL was withdrawn as 2000 mg dFdC are insoluble in these conditions. The different instillation conditions resulted in negligible plasma dFdC concentrations but significant differences in intracellular content and metabolism of dFdC. The lowest intratissue concentration of dFdC was detected in a 50 mL solution at a pH of 2.5-3.5 kept in the bladder for 1 h (standard arm). A pH 5.5 solution in 100 mL with a 2-h exposure favored the maximal intratumoral dFdC absorption which was 90 times higher than that recorded in the standard arm. CONCLUSIONS: The most commonly reported administration scheme of gemcitabine produced the lowest tissue bioavailability of dFdC. Other combinations of pH, dilution volume and duration of instillation proved more advantageous and merit testing in clinical trials.