Pharmacokin?tics of intravenous and oral cyclophosphamide in the presence of methotrexate and fluorouracil

Cyclophosphamide was administered to 12 breast cancer patients in combination with methotrexate and fluorouracil. Doses prescribed were cyclophosphamide 75 mg/m², methotrexate 30 mg/m² and fluorouracil 500 mg/m² (per square meter body surface). Cyclophosphamide was administered intravenously and orally in aqueous solutions and in tablets in a randomized cross-over trial. Methotrexate and fluorouracil were administered intravenously, methotrexate was given first and then fluorouracil. Assays of cyclophosphamide in blood plasma were performed by capillary gas chromatography. Data of mean bioavailability of cyclophosphamide administered by tablets were suggestive of sufficient absorption. In 2 patients, however, a lower bioavailability of cyclophosphamide was demonstrated. Intra-individual differences in the terminal slope of the plasma decay curves after intravenous and oral administration in some patients decreased the calculated bioavailability of cyclophosphamide, if these values were included in the calculation of cyclophosphamide bioavailability. Compared with the administration of the solutions peak times, lag-times and mean absorption times of cyclophosphamide given in tablets were markedly prolonged. It is concluded that interactions between cyclophosphamide and methotrexate and/or fluorouracil after oral dosing as tablets are different from interactions observed after intravenous administration of cyclophosphamide.