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Inhibition of first‐pass metabolism in cancer chemotherapy: Interaction of 6‐mercaptopurine and allopurinol
Author(s) -
Zimm Solomon,
Collins Jerry M,
O'Neill Dondra,
Chabner Bruce A,
Poplack David G
Publication year - 1983
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.1983.254
Subject(s) - allopurinol , xanthine oxidase , pharmacokinetics , pharmacology , chemistry , drug interaction , oral administration , mercaptopurine , first pass effect , xanthine oxidase inhibitor , chemotherapy , medicine , endocrinology , biochemistry , enzyme
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/m 2 and 75 mg/m 2 , 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 μM to a mean of 2.1 μM) and a 500% increase in man (0.74 μM to 3.7 μM). Allopurinol pretreatment also led to a 300% increase in plasma AUC in monkeys after oral 6‐MP (from a mean of 121 μM/min to a mean of 391 μM/min) and a 500% increase in AUC in man (from a mean of 142 μM/min to a mean of 716 μM/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. Clinical Pharmacology and Therapeutics (1983) 34 , 810–817; doi: 10.1038/clpt.1983.254