Pharmacokinetics of Mitomycin C in Dogs: Application of a High-Performance Liquid Chroma tograp h ic Assay

A normal-phase high-performance liquid chromatographic (HPLC) assay was developed for the determination of mitomycin C in plasma and urine. The method involves extraction of mitomycin C from plasma or urine into ethyl acetate-2-propanol-chloroform (70:15:15) with UV detection at 365nm. Quantitation was performed with an internal standard (porfiromycin) by the peak height ratio method. Excellent correlation was obtained between the HPLC assay and the established microbiological cup-plate bioassay. The pharmacokinetics of mitomycin C were investigated in beagle dogs following a 1-mg/kg iv (22-mg/m2) bolus dose. The plasma mitomycin C concentration versus time data were analyzed by using an open three-compartment model. The average volume of distribution was 1.90L or 17% of body weight for the central compartment and 7.7L or 68% of body weight for the terminal elimination phase. The volumes of distribution at steady state, calculated by model-dependent and -independent methods, compared very well with each other and were 6.5L or 58% of body weight. Total body clearance averaged 112 mL/min, and the mean terminal plasma half-life was 53min. The 0–24-h urinary excretion of intact mitomycin C accounted for 19% of the dose. The terminal half-life and percent urinary recovery of mitomycin C in dogs is similar to that in humans. Based on these observations, the dog appears to be a good model for studying the disposition of mitomycin C.