Pharmacokinetic profile of fotemustine in rat plasma by electrochemical detection

Abstract

1. A differential pulse polarographic (DDP) assay of diethyl-1-[3-(2-chloroethyl)-3-nitrosoureido] ethylphosphonate (fotemustine) was developed to determine 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 0dot;3 μg fotemustine/ml plasma and 1 μg/g in other tissues; the calibration curve in electrolyte or in plasma was linear between 0dot;5 and 100 μg/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 (4dot;0-7.3%). Tissue samples could be stored for 20 days at — 20°C without loss of the compound.

3. Plasma kinetics of fotemustine and BCNU given to male rats at therapeutic doses (20mg/kg i.v.) fitted a bi-exponential equation. Two minutes after injection plasma, levels of unchanged nitrosoureas were 15 and 11 μg/ml respectively. Fotemustine could be measured (0.92 μg/ml) for 3 h, while BCNU could not be detected after 60min. Unchanged fotemustine was cleared from the blood stream 3-5 times more slowly than BCNU.