Bone marrow depression 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. 

Both of these drugs are metabolized by xanthine oxidase, and concomitant administration of the xanthine oxidase inhibitor allopurinol leads to elevated plasma concentrations of 6-mercaptopurine that can cause significant bone marrow depression (132,133). 

Eosinophilia and leukocytosis are part of a general hypersensitivity reaction to allopurinol. Leukopenia and neutropenia are sometimes associated with allopurinol. Patients taking cytostatic therapy are more susceptible to bone marrow depression if they take allopurinol as well (SED-9, 155) however, this has not been confirmed in other reports (7). Agranulocjdosis is extremely rare. 

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). 

Allopurinol (4-hydroxypyrazolo [3, 4-d] pyrimidine) is an inhibitor of xanthine oxidase that was successfully introduced in the treatment of primary gout about 45 years ago [171]. Allopurinol continues to be accepted as standard therapy in the treatment of primary and secondary hyperuricemia. Adverse reactions occur in about 10% of patients treated with allopurinol and are relatively mild and self-limited [171,172]. A mild maculopapular eruption or gastrointestinal disorders are usually noted, which promptly regress with cessation of therapy. Isolated instances of allopecia [173], bone marrow depression [174], ocular lesions [175], acute cholangitis [176], various types of hepatic injuries [177,178] temporal arthritis [179], and xanthine stones [180] have been reported. Recently, LaRosa et al [180a] have reported a case of xanthine nephropathy during treatment of childhood T-cell ALL. 

There is some evidence to surest that the incidence of serious bone marrow depression caused by cyclophosphamide can be increased by allopurinol, but this was not confirmed in a controlled study. Allopurinol may prolong the half-life of cyclophosphamide and increase the levels of its cytotoxic metabolites. 

Boston Collaborative Drug Surveillance Programme. Allopurinol and cytotoxic drugs. Interaction in relation to bone marrow depression. JAMA (1974) 227,1036-40. 

Yet another problem may be encountered in the treatment of patients in whom severe renal damage has developed prior to correct diagnosis, and applies too in both uric acid and 2,8-DHA stone formers. Here the allopurinol dose must be reduced because oxipuri-nol, the active metabolite in vivo, is reabsorbed by the kidney and retained in excess in renal failure. The effective circulating levels are thus higher and the dose must be reduced accordingly, and oxipurinol levels in plasma monitored if possible,with the dose adjusted to keep circulating levels below 100 /xmol/litre (14). Oxipurinol will not only potentiate the action of immunosuppressive drugs such as azathioprine but can itself produce severe bone marrow depression (14). 

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