The pharmacokinetics of cyclophosphamide, phosphoramide mustard and nor-nitrogen mustard studied by gas chromatography in patients receiving cyclophosphamide therapy

Abstract

1 Simple, accurate and specific gas-chromatographic methods for the estimation of derivatized phosphoramide and non-nitrogen mustards utilizing alkali-flame ionization detection are described.

2 The pharmacokinetics in plasma of cyclophosphamide, phosphoramide mustard, nor-nitrogen mustard and nitrobenzyl pyridine alkylating activity were investigated following administration of cyclophosphamide by intravenous and oral routes to patients with malignant disease

3 The mean T_½ for cyclophosphamide was 8.88 h (s.d. 1.25 h) and the apparent volume of distribution (V_dβ) was 0.74 l kg^-1 (s.d. 0.16 l kg^-1).

4 The decline in plasma concentration of phosphoramide mustard was biphasic, the longer T_½ being 8.68 h (s.d. 2.50 h). This was not significantly different from that of cyclophosphamide. This could indicate that the true biological T_½ for phosphoramide mustard is identical with or shorter than that of cyclophosphamide.

5 The plasma concentrations of phosphoramide mustard following cyclophosphamide doses of known therapeutic efficacy are probably insufficient to produce important cytotoxic effects. This suggests that if phosphoramide mustard is the major alkylating metabolite derived from cyclophosphamide, it is transported in the blood in precursor form.

6 The mean plasma T_½ of nor-nitrogen mustard was 3.31 h (s.d. 1.60 h) which was significantly different from that of cyclophosphamide.

7 The mean plasma T_½ of the nitrobenzylpyridine alkylating activity was 9.81 h (s.d. 4.18 h) and did not significantly differ from that of cyclophosphamide. Although the area under the plasma alkylating activity concentration, time curve is related to the T_½ of cyclophosphamide, the alkylating activity does not reflect the concentrations of the two plasma metabolites measured.