Inhibition of first-pass metabolism in cancer chemotherapy: Interaction of 6-mercaptopurine and allopurinol

Abstract

Earlier studies suggested that the dose of [the antineoplastic drug] 6-mercaptopurine (6-MP) can be reduced substantially when the drug is given with allopurinol. The effect of allopurinol on the kinetics of oral and i.v. 6-MP was studied. Studies, conducted initially in rhesus monkeys and subsequently in man with 6-MP doses of 100 mg/m2 and 75 mg/m2, demonstrated that allopurinol pretreatment resulted in a nearly 400% increase in peak plasma concentration of oral 6-MP in monkeys (from a mean of 0.54 .mu.M to a mean of 2.1 .mu.M) and a 500% increase in man (0.74 .mu.M to 3.7 .mu.M). Allopurinol pretreatment also led to a 300% increase in plasma AUC [area under concentration-time curve] in monkeys after oral 6-MP (from a mean of 121 .mu.M/min to a mean of 391 .mu.M/min) and a 500% increase in AUC in man (from a mean of 142 .mu.M/min to a mean of 716 .mu.M/min). In contrast, allopurinol pretreatment had no effect on the kinetics of i.v. 6-MP. This difference was due to inhibition of 1st-pass metabolism of oral 6-MP as the result of the action of allopurinol on liver or intestinal xanthine oxidase. Although dose reduction of oral 6-MP given in conjunction with allopurinol is appropriate, it apparently is not necessary when 6-MP is injected i.v.