Basic Information
ID DDInter48 and DDInter150
Interaction Allopurinol may potentiate the pharmacologic effects of orally administered thiopurines. Severe bone marrow suppression and other toxicity have been associated with concomitant use of allopurinol and mercaptopurine (6-MP) or azathioprine, the latter of which is metabolized to 6-MP in vivo. The mechanism is thought to be allopurinol inhibition of 6-MP first-pass metabolism via hepatic or intestinal xanthine oxidase, the enzyme that catalyzes the inactivation of 6-MP. In one study, allopurinol pretreatment resulted in a nearly 500% increase in peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of oral 6-MP. No effect was observed on the pharmacokinetics of intravenous 6-MP. In a retrospective study of 24 heart and/or lung transplant patients receiving azathioprine, investigators found that 46% became leukopenic, 30% moderately anemic, and 22% thrombocytopenic within 3 months after starting allopurinol despite general compliance with thiopurine dosage reduction guidelines. Thus, decreasing the dosage by two-thirds or greater as often recommended does not abolish the risk of myelotoxicity.
Management Caution is advised if allopurinol must be used concomitantly with oral thiopurines. Most authorities recommend that thiopurine dosage be reduced to approximately 1/4 to 1/3 the usual dosage, and the patient closely monitored for hematologic and other toxicity. Subsequent doses should be adjusted based on therapeutic response and appearance of adverse effects. Patients should be advised to consult their physician if they develop signs and symptoms suggestive of thiopurine toxicity such as fever, chills, sore throat, fatigue, lethargy, pallor, anorexia, jaundice, dark urine, nausea, vomiting, signs of local infection, and unusual bleeding or bruising.
References [1] Brooks RJ, Dorr RT, Durie BG "Interaction of allopurinol with 6-mercaptopurine and azathioprine." Biomed 36 (1982): 217-22 [2] "Product Information. Purinethol (mercaptopurine)." Glaxo Wellcome, Research Triangle Pk, NC. [3] "Product Information. Imuran (azathioprine)." Glaxo Wellcome, Research Triangle Park, NC. [4] Cummins D, Sekar M, Halil O, Banner N "Myelosuppression associated with azathioprine-allopurinol interaction after heart and lung transplantation." Transplantation 61 (1996): 1661-2 [5] Kennedy DT, Hayney MS, Lake KD "Azathioprine and allopurinol: the price of an avoidable drug interaction." Ann Pharmacother 30 (1996): 951-4 [6] Venkat Raman G, Sharman Vl, Lee HA "Azathioprine and allopurinol: a potentially dangerous combination." J Intern Med 228 (1990): 69-71 [7] Cox GJ, Robertson DB "Toxic erythema of palms and soles associated with high-dose mercaptopurine chemotherapy." Arch Dermatol 122 (1986): 1413-4 [8] Zazgornik J, Kopsa H, Schmidt P, Kuschan K, Deutsch E "Increased danger of bone marrow damage in simultaneous azathioprine-allopurinol therapy." Int J Clin Pharmacol Ther Toxicol 19 (1981): 96-7 [9] Berns A, Rubenfeld S, Rymzo WT "Hazard of combining allopurinol and thiopruine." N Engl J Med 286 (1972): 730-1 [10] Coffey JJ, White CA, Lesk AB, Rogers WI, Serpick AA "Effect of allopurinol on the pharmacokinetics of 6-mercaptopurine (NSC 755) in cancer patients." Cancer Res 32 (1972): 1283-9 [11] Zimm S, Ettinger LJ, Holcenberg JS, Kamen BA, Vietti TJ, Belasco J, Cogliano-Shutta N, Balis F, Lavi LE, Collins JM, et al "Phase I and clinical pharmacological study of mercaptopurine administered as a prolonged intravenous infusion." Cancer Res 45 (1985): 1869-73 [12] Haagsma CJ "Clinically important drug interactions with disease-modifying antirheumatic drugs." Drugs Aging 13 (1998): 281-9 [13] Boyd IW "Allopurinol-azathioprine interaction." J Intern Med 229 (1991): 386 [14] Gearry RB, Day AS, Barclay ML, Leong RW, Sparrow MP "Azathioprine and allopurinol: A two-edged interaction." J Gastroenterol Hepatol 25 (2010): 653-5 [15] Kelley WN "Current therapy of gout and hyperuricemia." Hosp Pract 11 (1976): 69-76 [16] Zimm S, Collins JM, O'Neill D, Chabner BA, Poplack DG "Inhibition of first-pass metabolism in cancer chemotherapy: interaction of 6-mercaptopurine and allopurinol." Clin Pharmacol Ther 34 (1983): 810-7 [17] Krowka MJ, Breuer RI, Kehoe TJ "Azathioprine-associated pulmonary dysfunction." Chest 83 (1983): 696-8 [18] Schmidt LE, Dalhoff K "Food-drug interactions." Drugs 62 (2002): 1481-502
Alternative for Allopurinol M04A
Probenecid Lesinurad Rasburicase Sulfinpyrazone Pegloticase
Alternative for Azathioprine L04A
Deucravacitinib Teprotumumab Antithymocyte immunoglobulin (rabbit) Ocrelizumab Tildrakizumab Natalizumab
Eculizumab Efalizumab Sarilumab Pomalidomide Belatacept
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Potential Metabolism Interactions
Substrate-Substrate Interaction：If more than one drug is metabolized by the same CYP, it is possible that its metabolism is inhibited because of the competition between the drugs. That means, it can be useful to lower the dosage of the drugs in the drug-cocktail because they remain longer in the organism than in monotherapy.
Inhibitor-Inhibitor Interaction：Combining two or more inhibitors of one CYP, should be compensated by lowering the dosage of these drugs because the metabolism is reduced and the drugs remain longer in the organism than in monotherapy. Not adapting the dosage bears the risk of even more side effects.
Inhibitor-Substrate Interaction：Combining drugs that have inhibitory effect and are substrates of one particular CYP, should be compensated by lowering the dosage. They rest longer in the organism than in monotherapy. Not adapting the dosage bears the risk of even more side effects.