Allopurinol with mercaptopurine

The special risk is observed in patients with hepatic or renal impairment. It is not advised to use allopurinol in acute attacks of gout, but it is useful in chronic gout. Excretion of allopurinol and its active metabolite oxypurinol is primarily via the kidneys and therefore the dosage should be reduced if renal function is impaired. The adverse effects have been reported in patients receiving allopurinol with thiazide diuretics, particularly in patients with impaired renal function. The metabolism of azathioprine and mercaptopurine is inhibited by allopurinol and their doses should be reduced to one-quarter to one-third of the usual dose when either of them is given with allopurinol to avoid potentially life-threatening toxicity.27-29... 

MERCAPTOPURINE ANTIGOUT DRUGS -ALLOPURINOL t mercaptopurine levels with risk of toxicity (e.g. myelosuppression, pancreatitis) Azathioprine is metabolized to mercaptopurine. Allopurinol inhibits hepatic metabolism of mercaptopurine 1 doses of azathioprine and mercaptopurine by up to three-quarters and monitor FBC, LFTs and amylase carefully... 

The risk of bone marrow depression by cytostatic drugs is potentiated by allopurinol, which also appears to potentiate the therapeutic effect of purine cytostatic drugs, since it competitively inhibits their metabolic breakdown. Studies in animals suggest that this reaction occurs only with oral mercaptopurine (28), although there is older evidence that the toxicity of cyclophosphamide and other cytostatic drugs can be increased by allopurinol (SED-9, 156). The danger of combining allopurinol with azathioprine has been confirmed by cases of bone marrow suppression, particularly in patients with impaired renal function (SEDA-16,114). 

Xanthine oxidase in the small intestine and liver converts mercaptopurine to thiouric acid, which is inactive as an immunosuppressive. Inhibition of xanthine oxidase by allopurinol diverts mercaptopurine to more active metabolites such as 6-thioguanine and increases both immunosuppressive and potential toxic effects. Thus, patients on mercaptopurine should be warned about potentially serious interactions with medications used to treat gout or hyperuricemia, ami the dose should be decreased to 25% of the standard dose in subjects who are already taking allopurirwl. 

Profound pancytopenia developed in the first 3 of 13 children given maintenance treatment with meicaptopurine 2.5 mg/kg daily and allopuri-nol 10 mg/kg daily, but when the meieaptopurine dosage was halved, toxicity was manageable in the remaining 9 children. Severe leucopenia and thrombocytopenia occurred in another patient given allopurinol with standard dose mercaptopurine. ... 

Brooks RJ, Dorr RT, Durie BGM, Interaction of allopurinol with 6-mercaptopurine and azathioprine. Biomedicine (1982) 36, 217-22. 

The median dose of mercaptopurine in adults fell four- to fivefold after the addition of allopurinol lOOmg/day in 20 adults and children, with preferential metabolism of 6-mercaptopurine to 6-methylmercaptopurine [174 ]. Before the addition of allopurinol, six patients had mild rises in aminotransferase activities associated with high concentrations of methylmercaptopurine all subsequently had normalization with mercaptopurine dosage reduction. There were no adverse reactions, such as rash, renal failure, or pancreatitis, attributable to the combination of allopurinol and mercaptopurine. Three patients developed mild leukopenia after starting allopurinol. 

The daily dose of allopurinol is 300-600 mg. In combination with benzbromarone, the daily allopurinol dose is reduced to 100 mg. In general, allopurinol is well tolerated. The incidence of side effects is 2-3%. Exanthems, pruritus, gastrointestinal problems, and dty mouth have been observed. In rare cases, hair loss, fever, leukopenia, toxic epidermolysis (Lyell syndrome), and hqDatic dysfunction have been reported. Allopurinol inhibits the metabolic inactivation of the cytostatic dtugs azathioprine and 6-mercaptopurine. Accordingly, the administered doses of azathioprine and 6-mercaptopurine must be reduced if allopurinol is given simultaneously. 

There are several important drug-drug interactions with allopurinol. The effects of both theophylline and warfarin may be potentiated by allopurinol. Azathioprine and 6-mercaptopurine are purines whose metabolism is inhibited... 

Mercaptopurine (6-MP) is an oral purine analog that is converted to a ribonucleotide to inhibit purine synthesis. Mercaptopurine is converted into thiopurine nucleotides, which are catabolized by thiopurine S-methyltransferase (TPMT), which is subject to genetic polymorphisms and may cause severe myelosuppression. TPMT status may be assessed prior to therapy to reduce drug-induced morbidity and the costs of hospitalizations for neutropenic events. Mercaptopurine is poorly absorbed, with a time to peak concentration of 1 to 2 hours after an oral dose. The half-life is 21 minutes in pediatric patients and 47 minutes in adults. Mercaptopurine is used in the treatment of acute lymphocytic leukemia and chronic myelogenous leukemia. Significant side effects include myelosuppression, mild nausea, skin rash, and cholestasis. When allopurinol is used in combination with 6-MP, the dose of 6-MP must be reduced by 66% to 75% of the usual dose because allopurinol blocks the metabolism of 6-MP. 

Mercaptopurine—reduce dose by 75% when used in conjunction with allopurinol... 

The anticancer drug 6-mercaptopurine is deactivated by the enzyme xanthine oxidase. A cancer patient being treated with 6-meicaptopurine develops hyperuricemia, and the physician decides to give the patient allopurinoL... 

Absorption of thioguanine is incomplete and erratic. It is eliminated mainly by S-methylation. Thioguanine can be administered concurrently with allopurinol without reduction in dosage, unlike mercaptopurine and azathioprine. 

Azathioprine can be administered both orally and intravenously. It is well absorbed orally and after its rapid conversion to 6-mercaptopurine it is inactivated by xanthine oxidase which converts 6-mercaptopurine to 6-thiouric acid. This final metabolite is then excreted in the urine. In combination with the xanthine oxidase inhibitor allopurinol dose adjustments of azathioprine are needed. Renal disease also raises 6-mercaptopurine concentrations and can make dose adjustments necessary. Azathioprine is still used in organ transplantation programs and for the management of several autoimmune diseases. Its adverse effects include nausea, vomiting, diarrhea and, more seriously, bone marrow suppression and hepatotoxicity. Azathioprine is not thought to cause fetal malformation. 

Since allopurinol is metabolized by the hepatic microsomal drug-metabohzing enzymes, coadministration of drugs also metabohzed by this system should be done with caution. Because allopurinol inhibits the oxidation of mercaptopurine and azathioprine, their individual administered doses must be decreased by as much as 75% when they are given together with allopurinol. Allopurinol may also increase the toxicity of other cytotoxic drugs (e.g., vidarabine). The actions of allopurinol are not antagonized by the coadministration of salicylates. 

When chemotherapeutic mercaptopurines (eg, azathioprine) are given concomitantly with allopurinol, their dosage must be reduced by about 75%. Allopurinol may also increase the effect of cyclophosphamide. Allopurinol inhibits the metabolism of probenecid and oral anticoagulants... 

MP is converted to an inactive metabolite (6-thiouric acid) by an oxidation reaction catalyzed by xanthine oxidase, whereas 6-TG undergoes deamination. This is an important issue because the purine analog allopurinol, a potent xanthine oxidase inhibitor, is frequently used as a supportive care measure in the treatment of acute leukemias to prevent the development of hyperuricemia that often occurs with tumor cell lysis. Because allopurinol inhibits xanthine oxidase, simultaneous therapy with allopurinol and 6-MP would result in increased levels of 6-MP, thereby leading to excessive toxicity. In this setting, the dose of mercaptopurine must be reduced by 50-75%. In contrast, such an interaction does not occur with 6-TG, which can be used in full doses with allopurinol. 

Mercaptopurine is used in the treatment of acute lymphoid leukemia. Maintenance therapy makes use of both methotrexate and 6-mercaptopurine. Mercaptopurine is absorbed well from the gastrointestinal tract. It is metabolized through (1) methylation of the sulfhydryl group and subsequent oxidation, and (2) conversion to 6-thiouric acid with the aid of xanthine oxidase, which is inhibited by allopurinol. Mercaptopurine may cause hyperuricemia. Its chief toxicities are hepatic damage and bone marrow depression. 

Allopurinol is used not only in treating the hyperuricemia associated with gout, but also in the secondary hyperuricemia associated with the use of antineoplastic agents. However, allopurinol may interfere with the metabolism of antineoplastic agents such as azathioprine and 6-mercaptopurine. 

Aspirin, salicylates, and thiazide diuretics should not be used with allopurinol. The dose of mercaptopurine should be reduced one-third or one-fourth when used with allopurinol. Acute poisoning of colchicine should be treated with gastric lavage and activated charcoal administration. Supportive maintenance measures for blood pressure and respiration should be provided. Probenecid is used by athletes to inhibit the urinary excretion of banned anabolic steroids.85... 

Allopurinol specifically inhibits xanthine oxidase and thus prevents metabolism of azathioprine to mercaptopurine (with potentially dangerous toxicity). 

Allopurinol, a xanthine oxidase inhibitor, potentiates the action of mercaptopurine with danger of... 

Allopurinol prevents the oxidation of mercap-topurine to an inactive metabolite if an ordinary dose of mercaptopurine is given to a patient whose gout is being treated with allopurinol, dangerous potentiation occurs (see also azathiopurine, p. 292). 

Certain drugs inhibit non-microsomal metabolic pathways. Metronidazole, like disulfiram, inhibits aldehyde dehydrogenase, the enzyme that normally oxidizes acetaldehyde to acetic acid in the metabolic pathway for ethanol. Allopurinol inhibits xanthine oxidase, the enzyme that catalyses the oxidation of hypoxanthine to xanthine and xanthine to uric acid. Because azathioprine and 6-mercaptopurine are metabolized by xanthine oxidase, the dosage of these drugs (synthetic xanthine analogues), when used concomitantly with... 

---