Plasma concentrations of 4-hydroxycyclophosphamide and phosphoramide mustard in patients repeatedly given high doses of cyclophosphamide in preparation for bone marrow transplantation.

Plasma half-life and area under the curve (AUC) values for cyclophosphamide were determined in patients given this agent iv at doses of 50-60 mg/kg/infusion. Apparent plasma half-life and AUC values for the metabolites 4-hydroxycyclophosphamide and phosphoramide mustard were also determined in some of these patients. Disappearance from the plasma of the parent compound as well as that of the metabolites was approximately first-order. Plasma half-life values for cyclophosphamide ranged from 45 to 480 mins; AUC values ranged from 10 to 188 mM X min. As expected, AUC values for cyclophosphamide increased approximately linearly with an increase in its plasma half-life. Apparent plasma half-life values for 4-hydroxycyclophosphamide and phosphoramide mustard increased approximately linearly with an increase in plasma half-life values for cyclophosphamide; the slopes of these relationships were 1.35 and 1.97, respectively, but did not quite extrapolate to zero. AUC values for 4-hydroxycyclophosphamide and phosphoramide mustard remained approximately constant at about 5 and 15 mM X min, respectively, over the relatively wide range of plasma half-life and AUC values obtained for cyclophosphamide. On the basis of these observations we suggest that (a) changes in the rate of cyclophosphamide hydroxylation, effected by whatever means, will not alter the systemic therapeutic and toxic responses to a given dose of cyclophosphamide, given that the cytotoxic effects of this agent are directly proportional to AUC values of 4-hydroxycyclophosphamide and/or phosphoramide mustard, and (b) in most cases, 4-hydroxycyclophosphamide, and not phosphoramide mustard, is likely to be the circulating metabolite of therapeutic importance in humans since the AUC values for phosphoramide mustard exceeded those for 4-hydroxycyclophosphamide by only a factor of 3 and tumor and bone marrow cells proliferating in culture are generally substantially (8-25-fold) more sensitive to 4-hydroxycyclophosphamide.

PLasma half-life and urinary excretion of cyclophosphamide in children.

The plasma half-life and urinary excretion of cyclophosphamide were determined in 13 children who had various malignancies and/or who were being prepared for bone marrow transplantation. Disappearance from the plasma following iv infusion over a 1-2 hour period was first-order. Urinary excretion was maximal during the first 8 hours after administration and was essentially complete in 24 hours. The plasma half-life in children not receiving known inducers of hepatic microsomal mixed-function oxygenase activity or cyclophosphamide in the 3-week period prior to each determination ranged from 145 to 390 minutes. These values are lower than those ordinarily found in adult patients. The fraction of the total dose excreted in the urine as the parent compound ranged from 4% to 27%. Repeated administration of cyclophosphamide at approximately 30-60 day intervals did not appear to alter its plasma half-life but did appear to increase its urinary excretion. Daily administration of cyclophosphamide (approximately 50 mg/kg/day x 2 or 4) significantly decreased its plasma half-life and urinary excretion suggesting that it may reversibly induce its own metabolism.

Homotransplantation of the liver in a patient with hepatoma and hereditary tyrosinemia.

A girl with hereditary tyrosinemia, diagnosed at 6 months of age, was treated with a diet restricted in phenylalanine and tyrosine. At 9 1/2 years of age she developed an acutely enlarged liver and spleen, and the diagnosis of hepatocarcinoma was made. The patient received a liver transplant and tyrosine metabolites became normal while she was receiving a regular diet. Three months later, an infected thrombosis of the portal vein caused her death. Liver transplant appears to be an effective method of enzyme replacement in tyrosinemia and should be considered for prevention of hepatoma.