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Clinical Pharmacokinetics of Cyclophosphamide and Metabolites with and without SR-2508¹

School of Pharmacy, University of Southern California, Los Angeles, California 90033 [K. K. C. and P. S. H.], and University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin 53792 [K. D. T. and D. L. T.]

The pharmacokinetics of cyclophosphamide (CP) and several important metabolites was studied in detail in six patients receiving CP alone and with a radio- and chemosensitizing agent, SR-2508. CP at 1000 mg/m² was either infused in 20 min alone or given 2 h before an infusion of SR-2508 at 5 g/m² over 20 min, both separated by 3 weeks, to the same patients in a randomized fashion. Plasma and 24-h urinary levels of CP and four metabolites: [4-hydroxycyclophosphamide (4-OH CP), phosphoramide mustard (PM), chloroethyl oxazolidin-2-one, and alcophosphamide] were monitored by a gas chromatographic-mass spectrometric-stable isotope dilution assay. CP plasma levels were found to decline monoexponentially 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 µM and declined approximately in parallel to those of CP. The major circulating metabolite was found to be PM with a mean peak concentration of 40 µM and a terminal t_1/2 of 15 h. The mean area under the plasma concentration curve (AUC) ratios between metabolites and CP were: 4-OH CP, 0.0158; PM, 0.4518; and chloroethyl oxazolidin-2-one, 0.179 with alcophosphamide at low levels. No appreciable amount of nornitrogen mustard was 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 expressed as a percentage of CP dose. No statistically significant difference was detected in all standard pharmacokinetic parameters determined for both CP and metabolites between patients with CP alone and with SR 2508. Plasma 4-(p-nitrobenzyl)pyridine activity was found to correlate the closest with PM profiles, with respect to both standard pharmacokinetic parameters and AUC values. When plasma PM AUC values were plotted against AUC values of circulating 4-(p-nitrobenzyl)pyridine activity, a correlation co-efficient of 0.859 (P < 0.001) was obtained. Together with the significant cytotoxicity of PM these data support a significant contribution of circulating PM in the antitumor effect of PM.

¹ Supported in part by National Cancer Institute Core Grant 14089 (to the University of Southern California) and Contract CA 42325 (to the University of Wisconsin). Presented in part at the 81st Annual Meeting of the American Association for Cancer Research, Washington, DC, 1990.

² To whom requests for reprints should be addressed, at Room 308, Comprehensive Cancer Center, the Ohio State University, 410 W. 12th Avenue, Columbus, OH 43210.

³ Present address: Watson Laboratories, Corona, CA 91720.

⁴ Present address: University of Pittsburgh, Pittsburgh, PA 15213.

Received 3/14/94. Accepted 10/17/94.

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