ISSN:
1432-0738
Schlagwort(e):
1,2,2-Trimethylpropyl dimethylphosphinate
;
Analysis
;
Soman simulant
;
Pharmacokinetics
;
Soman
;
Partition coefficients
Quelle:
Springer Online Journal Archives 1860-2000
Thema:
Medizin
Notizen:
Abstract The soman simulant 1,2,2-trimethylpropyl dimethylphosphinate (PDP) antagonizes the therapeutic complications due to persistence of the nerve agent 1,2,2-trimethylpropyl methylphosphonofluoridate (soman) in rats. Using [13D]PDP or 1,2-dimethylpropyl dimethylphosphinate as an internal standard, we developed a gas chromatographic procedure for the analysis of PDP in aqueous solution and in blood samples. This procedure was used to investigate the pharmacokinetics of PDP in anaesthetized rats at intravenous doses of 2.0 and 0.6 mg/kg. The blood concentrations measured over a 420-min period can be described by a two-compartment open model with a rapid distribution phase (t1/2 = 4.3 min) and a rather slow elimination phase (t ss 1/2 = 2–3 h). The kinetics are approximately linear with dose. Under “steady state conditions”, PDP distributes evenly over the central and peripheral compartment (V dss = l.1–1.5 1.kg−1). At most 0.7% of intact PDP is renally excreted, which indicates that it is extensively metabolized. Since the partition coefficients (20° C) over n-octanol and water of PDP and soman are in the same range, i.e., 12 and 60, respectively, the much more rapid decrease in blood levels of C(±)P(−)-soman compared to PDP must be due to metabolic pathways of soman which are not available for PDP. At comparable doses, the blood level of PDP is initially 1 order of magnitude higher than that of C(±)P(−)-soman. This ratio increases in the course of 420 min to 4 orders of magnitude. Therefore, the kinetic conditions for which soman simulants were designed, i.e., to displace soman from reversible binding sites by means of a “mass effect”, are clearly fulfilled. However, hitherto unidentified effects other than competition between PDP and C(±)P(−)-soman for binding sites may also contribute to the beneficial effects of PDP pretreatment in soman intoxication.
Materialart:
Digitale Medien
URL:
http://dx.doi.org/10.1007/BF00316375
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