This study investigated gemcitabine administered intravesically to establish the local and systemic tolerability necessary for clinical trials. Gemcitabine was directly administered via catheter into the bladders of 24 male New Zealand rabbits weighing an average of 1.9±0.08 kg. Three groups received weekly gemcitabine for 5 (50 mg/kg) or 8 (25 mg/kg or controls) weeks. Animals were inspected daily for signs of toxicity and distress, body weight changes, and water and food consumption; electrocardiogram, blood pressure, and urinalysis were recorded before dosing and after 4 and 8 weeks of treatment. The rabbits were euthanized, and a full necropsy was performed on day 1 after the last instillation. Principal organs (spleen, thymus, testis, and muscle) and plasma samples were analyzed for the systemic absorption of gemcitabine. The 25-mg/kg dose was well tolerated with no clinical side effects. At 50 mg/kg, signs of mild myelosuppression and severe symptomatic toxicity (leg weakness, and hair and body weight loss) was evident after 3 weeks of treatment and three of the seven animals in this group died after four doses. Necropsies revealed normal bone marrow cellularity and organ histology at both doses. No significant systemic drug absorption was seen. These findings suggest that intravesical administration of gemcitabine does not produce organ-specific toxicity, but the higher dose (50 mg/kg) may represent the threshold above which increasing morbidity may occur.

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