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Therapeutic Efficacy of Cyclophosphamide as a Function of Inhibition of Its Metabolism¹

Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455

Experiments were designed to determine the Michaelis-Menten kinetic constants of cyclophosphamide metabolism in vitro in the presence of known inhibitors of rat hepatic microsomal mixed-function oxidase activity, the rate of cyclophosphamide metabolism in vivo in the presence of the most effective inhibitors of rat hepatic microsomal cyclophosphamide metabolism, the antitumor efficacy of cyclophosphamide as a function of its rate of activation, and the toxicity of cyclophosphamide as a function of its rate of activation. The hepatic microsomal mixed-function oxidase activation of cyclophosphamide was inhibited by all of the following compounds: 2-diethylaminoethyl-2,2-diphenylvalerate (SKF 525A), ethylmorphine, norcodeine, 7,8-benzoflavone, acetophenetidin, metyrapone, meperidine, testosterone, progesterone, estradiol-17ß, deoxycorticosterone, quinine, and probenecid. Compounds that did not inhibit cyclophosphamide activation included caffeine, folic acid, methotrexate, guanine, adenine, 6-mercaptopurine, 8-azaguanine, and 6-azauracil. Nitrogen mustard, chlorambucil, and bis(2-chloroethyl)amine hydrochloride did not inhibit hepatic microsomal mixed-function activity. The most effective competitive inhibitor was SKF 525A. Among the most effective noncompetitive inhibitors were the steroid hormones. In vivo cyclophosphamide metabolism in male rats paralleled in vitro metabolism. Thus, at early time points, blood levels of alkylating activity were decreased when SKF 525A or metyrapone were injected 45 min before cyclophosphamide was injected. Walker 256 carcinosarcoma cells were grown i.m. in the hindlegs of male rats, and the dose of cyclophosphamide that inhibited growth 50% was determined to quantitate antitumor efficacy. For estimation of the undesired toxicity of cyclophosphamide, peripheral blood leukocyte counts were made at intervals following the injection of cyclophosphamide. Pretreatment with metyrapone, 50 µmoles/kg, or SKF 525A, 10 µmoles/kg, 45 min before the administration of cyclophosphamide did not alter the therapeutic or toxic responses to cyclophosphamide. Pretreatment with SKF 525A, 50 µmoles/kg, increased the median effective dose of cyclophosphamide from 0.76 to 2.11 mg/kg and inhibited the magnitude of leukopenia due to cyclophosphamide. Administered by themselves, neither SKF 525A nor metyrapone had an effect on tumor growth or blood leukocyte levels. The data further demonstrate the futility of attempting to improve the therapeutic efficacy of cyclophosphamide by pretreatment with drugs that alter its rate of activation, and they also provide a rational basis for the ineffectiveness of such an effort.

¹ This research was supported by USPHS Grant GM 15477. Part of this material appeared in abstract form (21, 22). This is Paper 3 in the series on "Cyclophosphamide Metabolism."

Received 2/29/72. Accepted 5/19/72.

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