CLINICAL PHARMACOKINETICS OF CYCLOPHOSPHAMIDE AND METABOLITES WITH AND WITHOUT SR-2508

The pharmacokinetics of cyclophosphamide (CP) and several important me tabolites was studied in detail in six patients receiving CP alone and with a radio- and chemosensitizing agent, SR-2508. CP at 1000 mg/m(2) was either infused in 20 min alone or given 2 h before an infusion of SR-2508 at 5 g/m(2) over 20 min, both separated by 3 weeks, to the sa me patients in a randomized fashion. Plasma and 24-h urinary levels of CP and four metabolites: [4-hydroxycyclophosphamide (4-OH CP), phosph oramide mustard (PM), chloroethyl oxazolidin-2-one, and alcophosphamid e] were monitored by a gas chromatographic-mass spectrometric-stable i sotope dilution assay. CP plasma levels were found to decline monoexpo nentially with the appearance of transient saturation kinetics in some and a mean t(1/2) of 5.2 h for patients treated with CP alone. Plasma 4-OH CP levels showed a mean peak concentration of 2.4 mu M and decli ned approximately in parallel to those of CP. The major circulating me tabolite was found to be PM with a mean peak concentration of 40 mu M and a terminal t(1/2) of 15 h. The mean area under the plasma concentr ation curve (AUG) ratios between metabolites and CP were: 4-OH CP, 0.0 158; PM, 0.4518; and chloroethyl oxazolidin-2-one, 0.179 with alcophos phamide at low levels. No appreciable amount of nornitrogen mustard wa s detected. Mean urinary excretion was: CP, 10.8; 4-OH CP, 0.5; PM, 39 .0; alcophosphamide, 0.4; and chloroethyl oxazolidin-2-one, 3.0, all e xpressed as a percentage of CP dose. No statistically significant diff erence was detected in all standard pharmacokinetic parameters determi ned for both CP and metabolites between patients with CP alone and wit h SR 2508. Plasma 4-(p-nitrobenzyl)pyridine activity was found to corr elate the closest with PM profiles, with respect to both standard phar macokinetic parameters and AUC values. When plasma PM AUC values were plotted against AUC values of circulating 4-(p-nitrobenzyl)pyridine ac tivity, a correlation coefficient of 0.859 (P < 0.001) was obtained. T ogether with the significant cytotoxicity of PIM these data support a significant contribution of circulating PM in the antitumor effect of PM.