Self-induction of Cyclophosphamide and Ifosfamide Metabolism by Repeated High-Dose Treatment

Abstract

SummaryIn 4 patients with aplastic anemia, receiving 50 mg/kg B. W. cyclophosphamide (CP) for 4 days as a conditioning treatment for bone marrow transplantation, CP half-life was shortened from 7.3 ± 1.3 h to 4.3 ± 1.0 h during treatment. In 7 leukemic patients (60 mg/kg B. W.), CP half-life decreased from 4.7 ± 1.3 h to 3.0 ± 10.4 h on day 2. Since the peak levels of activated CP were elevated at the same time and urinary excretion of the parent drug did not change significantly, the shortening of CP half-life is obviously due to a self-induction of CP activation in the liver. Similar observations of an induction of the activation rate, only to a smaller extent, were made for the CP analogue ifosfamide (IFO) in man. During treatment of bronchogenic carcinoma with 2 g/m2 B. S. A. IFO in 6 patients, a decrease of IFO-half-life from 6.4 h to 5.3 h after the second dose was measured. Results were confirmed in NMRI mice. After pretreatment with whole-body irradiation (8 Gy, as used in bone marrow transplantation), self-induction of CP metabolism was abolished, but formation of activated metabolites was not restricted. During CP therapy of breast cancer in 12 patients with a low dosage of 175 mg/m2 B. S. A., no change in CP half-life could be detected during drug administration on 4 consecutive days (4.16/4.01/4.14/3.95 h). Thus, acceleration of CP and IFO metabolism during short-term treatment occurred only within a high-dosage range. The remarkable influence of different drug dosages on CP and IP metabolism may result in a different drug toxicity and tumor response.