TRIS(2-CHLOROETHYL) PHOSPHATE PHARMACOKINETICS IN THE FISCHER-344 RAT- A COMPARISON OF CONVENTIONAL METHODS AND IN-VIVO MICRODIALYSIS COUPLED WITH TANDEM MASS-SPECTROMETRY

The pharmacokinetics of tris(2-chloroethyl) phosphate (TRCP, 20 mg/kg, iv) were investigated in awake male and female and anesthetized male Fischer 344 (F344) rats by conventional (CONV) sampling/detection meth ods (blood withdrawal with sample workup and analysis for TRCP). TRCP pharmacokinetics were also investigated in anesthetized male F344 rats using a new sampling/detection technique, in vivo microdialysis coupl ed with tandem mass spectrometry(1) (MD/MS/MS). The concentration of f ree TRCP in plasma versus time profiles were analyzed using noncompart mental methods to estimate pharmacokinetic parameters. Comparisons of mean parameter estimates were made for (1) awake males versus females in CONV studies (t test, no significant differences, p less than or eq ual to 0.05) and (2) awake and anesthetized males in CONV studies and anesthetized males in MD/MS/MS studies. There were significant differe nces (Scheffe's test) for the three groups of male rats, most notably the free TRCP concentration in plasma at early time points in CONV ver sus MD/MS/MS studies. The contributions of an indwelling jugular cannu la, the blood sampling regimen, and the in vitro MD/MS/MS standard cal ibration curve were investigated. It appears that quantitation of TRCP by mass spectrometry using an in vitro standard calibration is respon sible for the difference.