Abstract
The effect of phenobarbital or 2-diethylaminoethyl-2,2-diphenylvalerate (SKF 525A) on the activation of cyclophosphamide in mice was examined. Cyclophosphamide was injected into BDF1 male mice pretreated with phenobarbital or SKF 525A at various time intervals before and simultaneously with implantation of leukemia L1210 cells. The mean survival times were used as the parameter to study the retention of the antileukemic activity of the drug. In a parallel experiment with a chemical procedure the quantity of the alkylating metabolites of cyclophosphamide in plasma was determined at various time intervals after cyclophosphamide administration. The results of the chemical experiments showed that pretreatment with phenobarbital accelerated the production of alkylating metabolites of cyclophosphamide followed by a rapid depletion of the alkylating drug. Pretreatment with SKF 525A retarded the activation process which resulted in the slow release of the drug over a longer period of time. The biological experiments indicated that the duration of antileukemic activity was shortened by phenobarbital and lengthened by SKF 525A. The similarity of the results of the biological and chemical studies relating to the effect of pretreatment on the metabolism of cyclophosphamide suggests that the metabolites of cyclophosphamide measured by the chemical assay are responsible for the antileukemic activity. The chemical data show that pretreatment with SKF 525A increased and pretreatment with phenobarbital decreased the total amount of alkylating metabolites. In studying combination chemotherapy with drugs that influence cyclophosphamide activation, the chemical and biological procedures reported here are useful tools in evaluating the effects of these drugs on cyclophosphamide therapy.
Footnotes
- Received June 17, 1971.
- Accepted October 9, 1971.
- © 1972 by The Williams & Wilkins Co.
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