Water intoxication in man after cyclophosphamide therapy: Time course and relation to drug activation

Cyclophosphamide therapy in doses greater than 50 mg/kg body weight has resulted in frank impairment of water excretion in 17 of 19 normally hydrated patients with cancer. Clinically, these patients developed hyponatremia, weight gain, and inappropriately concentrated urine during cyclophosphamide infusion, but without cyclophosphamide they excreted water loads normally. The decrease in serum osmolarity (range, 5 to 41 milliosmols/litre) and rise in urine osmolarity (range, 309 to 798 milliosmols/litre) occurred 4 to 12 hours after cyclophosphamide infusion, lasted up to 20 hours, and was related temporally with the urinary excretion of active alkylating metabolite(s) of the drug. Treatment of four cancer patients with cytosine arabinoside failed to provoke water intoxication. The mechanism of cyclophosphamide induced impairment of water excretion is unclear. Tumor release of antidiuretic hormone after cyclophosphamide administration seems unlikely since the study group included patients with leukemia and aplastic anemia without tumor. The likelihood and self limited time course of impaired water excretion during high dose cyclophosphamide treatment should be recognized because such patients are invariably waterloaded to prevent uric acid lithiasis and drug related cystitis.