Pharmacokinetic profile of fotemustine in rat plasma by electrochemical detection.
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 0.3 micrograms fotemustine/ml plasma and 1 microgram/g in other tissues; the calibration curve in electrolyte or in plasma was linear between 0.5 and 100 micrograms/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 greater than kidney greater than plasma greater than brain greater than 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 micrograms/ml respectively. Fotemustine could be measured (0.92 microgram/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.
Bartosek
I
I
Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Corada
M
M
Dallarda
S
S
Lucas
C
C
Deloffre
P
P
Guaitani
A
A
D000818:Animals; D001921:Brain / Q000378:metabolism; D002330:Carmustine / Q000097:blood / Q000493:pharmacokinetics; D004563:Electrochemistry; D006863:Hydrogen-Ion Concentration; D007668:Kidney / Q000378:metabolism; D007700:Kinetics; D008027:Light; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D009607:Nitrosourea Compounds / Q000097:blood / Q000493:pharmacokinetics*; D009943:Organophosphorus Compounds / Q000097:blood / Q000493:pharmacokinetics*; D011048:Polarography; D051381:Rats; D013696:Temperature
D009607:Nitrosourea Compounds; D009943:Organophosphorus Compounds; C054368:fotemustine; D002330:Carmustine