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Effects of pH and Temperature on the Stability and Decomposition of N,N'N''-Triethylenethiophosphoramide in Urine and Buffer¹

Division of Developmental Therapeutics, University of Maryland Cancer Center, Baltimore, Maryland 21201

N,N',N''-Triethylenethiophosphoramide (thiotepa) was dissolved at 100 µg/ml in urine or in 0.1 M sodium acetate buffer and incubated at 37° or 22°. After 0, 15, 30, 60, 90, and 120 min of incubation, 0.1-ml samples were extracted into ethyl acetate and analyzed by gas-liquid chromatography (1.8-m x 2-mm column packed with 3% OV225 on 100/120 Supelcoport; oven at 180°; injection port and nitrogen-phorphorus detector at 230°). Thiotepa was more stable at 22° than at 37° and at pH 6 to 7 than at pH 4 to 5.5. After 2 hr of incubation at 37°, thiotepa concentrations decreased by 40% at pH 5.0 but only 10% at pH 6 or 7. Although thiotepa concentrations declined as described above, alkylating activity, as assessed by p-nitrobenzyl pyridine reactivity, was stable at all temperatures and pHs tested. Partition coefficients of thiotepa degradation products into toluene, ethyl acetate, diethyl ether, and hexane were determined after 0 and 120 min of incubation in urine at pH 4.0. The extractability of alkylating activity into these organic solvents decreased dramatically after 120 min. Thiotepa degradation products were extracted from urine at pH 4.0 after 0, 30, 60, and 120 min incubation at 37° and were separated by thin-layer chromatography. In addition to thiotepa (R_f 0.15), 3 degradation products possessing p-nitrobenzyl pyridine alkylating activity (R_f 0.35, 0.52, and 0.60) were observed during the course of incubation. The structures of the materials with R_f 0.35 and 0.52 were identified by mass spectrometry and indicated that thiotepa degradation occurs by successive addition of HCl molecules with opening of the aziridine rings and conversion to 2-chloroethyl moieties.

¹ This work was supported by grants from Lederle Laboratories and the Bressler Foundation.

² To whom requests for reprints should be addressed.

Received 1/25/84. Accepted 6/25/84.

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