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Pharmacological and Biochemical Effects of Pyrazofurin in Humans¹

Department of Neoplastic Diseases, Mount Sinai School of Medicine, New York, New York 10029

After administration of Pyrazofurin (PF) in a dose range of 100 to 300 mg/sq m as a single i.v. bolus in patients with cancer, the drug distributed to a central compartment of approximately 150% of the total body water distribution. The initial plasma half-life was about 0.17 hr. The serum decay of the elimination phase was too slow to calculate from available data. Less than 12% of the administered PF was recovered from urine. Administration of PF at a dose of 250 mg/sq m, either as an i.v. bolus or as a 24-hr infusion, resulted in a fall of ¹⁴CO₂ production from [7-¹⁴C]orotic acid ("orotic acid metabolism") in normal and leukemic leukocytes to less than 10% of the pretreatment level on Day 2 or 3, followed by a gradual return to normal in 5 to 9 days. In some instances the recovery was much slower.

Administration of PF was also followed by urinary excretion of orotidine and orotic acid. The amount of urinary pyrimidine excretion was dose related and tended to be larger after a 24-hr infusion than after an i.v. bolus of the identical dose, although the recovery rate of the orotic acid metabolism in leukocytes seemed similar. PF was found to be uricosuric.

The long plasma half-life of the elimination phase of PF and the prolonged effects on the biochemical target indicate that the drug can best be administered intermittently. The apparently large distribution and low urinary excretion of PF imply extensive tissue uptake or biotransformation.

¹ Supported by USPHS Research Grant CA 15936-03 from the National Cancer Institute, NIH, Department of Health, Education and Welfare.

Received 12/22/76. Accepted 4/ 6/77.