Antineoplastic drugs are widely used in the United States. An estimated 50,000 cases are cured each year with chemotherapy. However, in many patients, treatment is ineffective or life-threatening toxicity is seen. Abnormal pharmacokinetics in an individual patient may be one cause for a poor therapeutic response. Recent studies have demonstrated that the rate of microsomal metabolism of certain drugs is under genetic control. From 3-8% of the Caucasian population has been found to be missing a specific cytochrome P-450 hepatic microsomal isoenzyme. These persons metabolize certain drugs more slowly than normals. This can result in either increased toxicity or decreased therapeutic effectiveness depending on whether the parent drug or a metabolite is the active compound. The goal of our laboratory is to determine if the rate of metabolism of some antineoplastic agents might be genetically controlled. Initial studies will use cyclophosphamide as a model drug as: 1) it undergoes hepatic microsomal metabolism and 2) it is commonly used drug so that a clinical study is feasible. In vitro studies of cyclophosphamide metabolism are planned to identify the cytochrome P-450 isoenzyme involved in its activation. Preliminary clinical studies are designed to: 1) investigate the possibility that poor metabolizers of debrisoquine or mephenytoin (two drugs whose metabolism has been shown to be under genetic control) may also be poor metabolizers of cyclophosphamide and 2) to develop a limited- sampling method for quantitating cyclophosphamide kinetics so that a large scale clinical study evaluating a genetic basis for this drug's metabolism can be subsequently undertaken. Identification of patients who have an altered rate of cyclophosphamide metabolism will allow better therapeutics use of this drug and will hopefully serve as a model for other drugs.
| Anthony, L B; Long, Q C; Struck, R F et al. (1990) The effect of cimetidine on cyclophosphamide metabolism in rabbits. Cancer Chemother Pharmacol 27:125-30 |
