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The Comparative Physiological Disposition of ThioTEPA and TEPA in the Dog^*

( Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Mich.)

A sensitive, specific fluorometric method for the determination of N,N',N''-triethylenethiophosphoramide (thioTEPA) and N,N',N''-triethylenephosphoramide (TEPA), separately and in the presence of each other, has been developed. The percentage recovery of thioTEPA or TEPA added to plasma and urine in the range of 0.05–0.2 µg/ml was 95 ± 20 per cent, and at levels of 0.2 µg-2.0 µg/ml it was 90 ± 12 per cent.

After the intravenous or oral administration of thioTEPA to dogs the presence of TEPA in the urine was demonstrated both by analytical procedures and by means of paper chromatography. After 3.0 mg/kg intravenously, the percentage excretion of TEPA was 8–13 per cent of the administered dose of thioTEPA. After 6.0 mg/kg orally, the percentage excretion of TEPA was 13–15 per cent. The plasma concentration curves of thioTEPA after 3.0 mg/kg intravenously fell rapidly to a level of 0.2 µg/ml in 2 hours. On the other hand, maximal plasma levels (1.2–1.4 µg/ml) of TEPA were not reached until 90 minutes to 2 hours. On the basis of information on plasma levels and urinary excretion of thioTEPA, at least 50 per cent of the administered dose was absorbed.

Prior administration of ß-diethylaminoethyldiphenyl propyl acetate HCl (SKF 525A) delayed the conversion of thioTEPA to TEPA. This delay in conversion was accompanied by an increased toxicity in mice and dogs.

When TEPA was administered to dogs in a dose of 3.0 mg/kg intravenously, the plasma levels were 2–4 times the levels of thioTEPA after intravenous administration. The urinary recovery of TEPA was 24–34 per cent of the administered dose.

The stability of thioTEPA and TEPA in various media was investigated. There was no significant difference between the two drugs upon incubation in plasma, whole blood, or various buffers. Both drugs were stable in alkaline medium (pH 8.4) and were rapidly destroyed in acid medium (pH 4.2).

Tissue distribution of thioTEPA could not be determined, because the drug was almost completely destroyed when in contact with tissue. TEPA, on the other hand, could be determined and displayed a marked affinity for bone marrow as compared with other tissues.

^* This project was supported by USPHS Grant No. CY-2992 of the National Institutes of Health.

Received 11/16/59.

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