Abstract
Oxipurinol, the major metabolite of allopurinol, decreased the toxicity of 5‐fluorouracil (5‐FU) to human granulocyte colony‐forming units in vitro by a factor of four. The ability of allopurinol to reduce 5‐FU toxicity in vivo was studied in 23 advanced cancer patients during 42 courses of treatment. 5‐FU was administered by continuous intravenous infusion for five days; allopurinol, 300 mg, po, every 8 hours was started 2 hours before and continued during and for 24 hours after 5‐FU infusion. 5‐FU was escalated from 1.5 to 2.25 g/m2/day on separate courses; the dose‐limiting toxicity was mucositis which occurred at a level of 2.0 g/m2/day. At a 5‐FU dose rate of >2.0 g/m2/day 5‐FU pharmacokinetics were nonlinear, reflecting saturation of catabolic pathways, and the steady‐state 5‐FU serum concentration was approximately 4 times that which was tolerable without allopurinol. At these concentrations of 5‐FU oxipurinol significantly influenced the clearance of 5‐FU. Thus concurrent allopurinol therapy permitted a doubling of the maximum tolerated dose of 5‐FU and a four‐fold increase in the tolerated concentration x time exposure to 5‐FU.