Inhibition of first-pass metabolism in cancer chemotherapy: interaction of 6-mercaptopurine and allopurinol.
Earlier studies suggested that the dose of 6-mercaptopurine (6-MP) can be reduced substantially when the drug is given with allopurinol. We studied the effect of allopurinol on the kinetics of oral and intravenous 6-MP. 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 microM to a mean of 2.1 microM) and a 500% increase in man (0.74 microM to 3.7 microM). Allopurinol pretreatment also led to a 300% increase in plasma AUC in monkeys after oral 6-MP (from a mean of 121 microM/min to a mean of 391 microM/min) and a 500% increase in AUC in man (from a mean of 142 microM/min to a mean of 716 microM/min). In contrast, allopurinol pretreatment had no effect on the kinetics of intravenous 6-MP. This difference was found to be due to inhibition of first-pass metabolism of oral 6-MP as the result of the action of allopurinol on liver or intestinal xanthine oxidase. Our results indicate that, although dose reduction of oral 6-MP given in conjunction with allopurinol is appropriate, it is not necessary when 6-MP is injected intravenously.
D000284:Administration, Oral; D000493:Allopurinol / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001682:Biological Availability; D004347:Drug Interactions; D006801:Humans; D007275:Injections, Intravenous; D007700:Kinetics; D007945:Leukemia, Lymphoid / Q000188:drug therapy / Q000378:metabolism; D008253:Macaca mulatta; D015122:Mercaptopurine / Q000378:metabolism* / Q000627:therapeutic use; D008657:Metabolic Clearance Rate; D013045:Species Specificity
D000493:Allopurinol; D015122:Mercaptopurine