Phenobarbital Effects on Cyclophosphamide Pharmacokinetics in Man

Plasma concentrations and urinary excretion rates of cyclophosphamide and its total metabolites were measured after i.v. administration of 500-to 1000-mg doses of radiolabeled cyclophosphamide to four patients. The data obtained before and after phenobarbital treatment were analyzed pharmacokinetically with the use of a two-compartment open model. Phenobarbital had no quantitatively important effects on the distribution and renal excretion of cyclophosphamide. The rate of biotransformation of the inactive precursor to its total metabolites was increased 2-to 3-fold by phenobarbital. However, because biotransformation is the predominant pathway of cyclophospharnide disposition, the total quantity of metabolites formed was only increased slightly by phenobarbital. These observations, together with comprehensive data in the literature showing that phenobarbital has little effect on the chemotherapeutic properties of cyclophosphamide in several animal tumor systems, indicate that phenobarbital treatment should modify only slightly the efficacy and toxicity of cyclophosphamide in man.