PHARMACOKINETIC PROFILE OF FOTEMUSTINE IN RAT PLASMA BY ELECTROCHEMICAL DETECTION

1. A differential pulse polarographic (DDP) assay of diethyl-1-[3-(2-chloroety)-3-nitrosoureido] ethylphosphonate (fotemustine) was developed to determin the kinetics of this nitrosourea in plasma, brain, liver, lung and kidney. The optimized polarographic determination, previously applied to BCNU and CCNU, attained a limit of detection of 0.3-mu-g foremustine/ml plasma and 1-mu-g/g in other tissues; the calibration curve in electrolyte or in plasma was linear between 0.5 and 100-mu-g/ml. 2. The choice of electrolyte, the effects of pH, temperature, light, and the stability of fotemustine in samples were investigated. Recovery of fotemustine was 76-90% from lung > kidney > plasma > brain > liver; the variability coefficients were low (4.0-7.3%). Tissue samples could be stored for 20 days at -20-degrees-C without loss of the compound. 3. Plasma kinetics of fotemustine and BCNU given to male rats at therapeutic doses (20 mg/kg i.v.) fitted a bi-exponential equation. Two minutes after injection plasma, levels of unchanged nitrosoureas were 15 and 11-mu-g/ml respectively. Fotemustine could be measured (0.92-mu-g/ml) for 3 h, while BCNU could not be detected after 60 min. Unchanged fotemustine was cleared from the blood stream 3-5 times more slowly than BCNU.