The human pharmacology of cyclophosphamide was investigated in 26 patients who received cyclophosphamide 14C in doses of 6 to 80 mg/kg i.v. Levels of the intact drug in plasma and urine and excretion of 14C label in breath and stools were determined by liquid scintillation counting. Plasma and urine alkylating activity was measured by reaction with 4-(4-nitrobenzyl)pyridine. Protein binding of cyclophosphamide and plasma alkylating metabolites were determined by plasma ultrafiltration.

Injected cyclophosphamide distributed rapidly into 64% of body weight, and plasma cyclophosphamide half-life in patients without prior drug exposure was 6.5 hr. Not more than 20% of injected cyclophosphamide was excreted intact in urine at any dose level.

Plasma alkylating metabolites were 56% bound to plasma proteins. After a 40-mg/kg dose, peak unbound alkylating activity averaged 13.3 mµmoles/ml, and in most patients at this dose alkylating activity in the plasma was measurable for 24 hr. Sixty-eight % of injected 14C label was excreted in urine. Breath and fecal excretion were negligible.

In a regimen of five consecutive daily cyclophosphamide administrations, cyclophosphamide half-life was shorter and peak alkylating levels were constantly higher on the 5th day than on the 1st day. Prior patient treatment with allopurinol resulted in significantly longer cyclophosphamide half-life, but concomitant prednisolone treatment had no effect. The effect of hepatic metastases on cyclophosphamide metabolism was unclear. Moderate renal failure in one patient resulted in prolonged retention of alkylating materials in plasma and severe toxicity.

Although patients with and without prior exposure to microsomal enzyme-inducing drugs demonstrated marked variation in plasma cyclophosphamide half-life and peak alkylating levels, the total concentration × time product remained relatively constant for a given cyclophosphamide dose, suggesting that alterations in the rate of cyclophosphamide metabolism by drugs or liver metastases in the absence of renal failure will not change toxicity or therapeutic effect.

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