Therapeutic Efficacy of Cyclophosphamide as a Function of Its Metabolism1

Experiments were designed to investigate the metabolism of Cyclophosphamide in vitro and in vivo following the administration of known stimulators and depressors of rat hepatic microsomal mixed-function oxidase activity, the antitumor efficacy of Cyclophosphamide as a function of its metabolism, and the toxicity of Cyclophosphamide as a function of its metabolism. Regarding the metabolism of Cyclophosphamide by hepatic microsomal preparations, the following observations were made, (a) Pretreatment with phénobarbital of male and female rats and of female mice increased the rate of metabolism 7-, 23-, and 7-fold, respectively, (b) pretreatment of male rats with 3-methylcholanthrene depressed metabolism to 33% of that of controls, but similar pretreatment of female mice did not alter the rate of metabolism, (c) The Km for Cyclophosphamide INTRODUCTION in their subsequent return to normal levels was observed between control male rats; female rats; and phénobarbital-, 3-methylcholanthrene-, or cobalt chloride-pretreated male rats. Pretreatment with phénobarbital did accelerate leukocyte depression and also increased the magnitude of depression. In methylcholanthrene-pretreated male rats and in female rats, the magnitude of depression was somewhat less and recovery rates were somewhat altered. Administered by itself, phénobarbital, 3-methylcholanthrene, or cobalt chloride had no effect on tumor growth or blood leukocyte levels. The data demonstrate the futility of trying to improve the therapeutic efficacy of Cyclophosphamide by pretreatment with drugs that alter its rate of activation. In addition, the data provide a rational basis for the ineffectiveness of such an effort.