Myelosuppression with azathioprine

Azathioprine, mycophenolate mofetil, and enteric-coated MPA are not metabolized through the CYP isozyme system therefore, they do not experience the same DDI profiles as cyclosporine, tacrolimus, and sirolimus. Azathioprine s major DDIs involve allopurinol, angiotensin-converting enzyme (ACE) inhibitors, aminosalicylates (e.g., mesalamine and sulfasalazine), and warfarin.11 The interaction with allopurinol is seen frequently and has clinical significance. Allopurinol inhibits xanthine oxidase, the enzyme responsible for metabolizing azathioprine. Combination of azathioprine and allopurinol has resulted in severe toxicities, particularly myelosuppression. It is recommended that concomitant therapy with azathioprine and allopurinol be avoided, but if combination therapy is necessary, the azathioprine doses must be reduced to one-third or one-fourth of the current dose. Use of azathioprine with the ACE inhibitors or aminosalicylates also can result in enhanced myelosuppression.11 Some case reports exist demonstrating that warfarin s therapeutic effects may be decreased by azathioprine.43-45... 

The use of myelosuppressive agents, such as cotrimoxazole and valganciclovir, also could enhance myelosuppression when combined with azathioprine or the MPA derivatives. 

Colombel, J. F., Ferrari, N., Debuysere, H., et al. (2000) Genotypic analysis of thiopuiine S-methyltransferase in patients with Crohn s disease and severe myelosuppression during azathioprine therapy. Gastroenterology. 118, 1025-1030. 

Increased risk of myelosuppression with clozapine, azathioprine, cisplatin, methotrexate... 

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... 

Cummins D, Sekar M, Halil O, Banner N. Myelosuppression associated with azathioprine-allopuri-nol interaction after heart and lung transplantation. Transplantation 1996 61(ll) 1661-2. 

The antiproliferatives azathioprine and the mycophenohc acid derivatives inhibit T cell proliferation. Myelosuppression is the most significant adverse event associated with these agents. 

Immunosuppressants such as azathioprine and mercaptopurine have a significant potential for adverse reactions, including bone marrow suppression, and have been associated with lymphomas (in renal transplant patients) and pancreatitis. Myelosuppression resulting in leukopenia is related to a deficiency in TPMT in some patients. 

Tests for the TPMT genotype and phenotype are commercially available. Attention should be paid for those patients who test negative for TPMT status. Patients with poor or intermediate TPMT activity may tolerate only 1/10 to 1/2 of the average 6-MP dose. A pharmacoeconomic model has been developed to analyze the potential cost of screening to prevent azathioprine toxicity. In this model, it was assumed that TPMT deficiency is present in 0.3% of the population, that intermediate activity is present in 11%, and that both groups have an increased risk of developing myelosuppression. Under these circumstances, the model predicted that the costs per Caucasian patient for the first 6 mo of therapy with screening are lower... 

Fig. 13.2 Thiopurine methyl transferase (TPMT) methylator genotypes in Crohn s disease during azathioprine/6-mercaptopurine (AZA/6-MP) treatment influences the time in months to development of severe myelosuppression. However, only 27% of patients with Crohn s disease and myelo-suppression during AZA therapy had mutant alleles of the TPMT gene associated with enzyme deficiency. Myelosuppression is more often caused by other factors. Continued monitoring of blood cell counts remains mandatory in patients treated with AZA. (Reproduced from ref 35.)...

The metabolism of azathioprine is bimodal in humans, with rapid metabolizers clearing the drug four times faster than slow metabolizers. Production of 6-thioguanine is dependent on thiopurine methyltransferase (TPMT), and patients with low or absent TPMT activity (0.3% of the population) are at particularly high risk of myelosuppression by excess concentrations of the parent drug if dosage is not adjusted. 

Azathioprine Myelosuppression, hepatoxicity, lymphoprol iterative disorders CBC, platelet count, creatinine, AST or ALT Symptoms of myelosuppression CBC and platelet count every 1-2 weeks with changes in dose (every 1-3 months thereafter), AST yearly. Pap test at regular intervals... 

Azathioprine, a purine analogue, is another systemic immunosuppressant that may be helpful in severe cases of AD. Its main disadvantage, compared with cyclosporine, is a delayed onset of action of 4 to 6 weeks. Most reports of azathioprine use have been in uncontrolled, open, retrospective trials, and the use of inconsistent regimens in these trials makes determination of dosing schedules difficult. Despite numerous adverse effects—including myelosuppression, hepatotoxic-ity, and gastrointestinal disturbances—azathioprine can be helpful in reduction of AD disease activity. ... 

Drug Interactions Xanthine oxidase, a key enzyme in the catabolism of azathioprine metabolites, is blocked by aUopurinol. If azathioprine and allopurinol are used concurrently, the azathioprine dose must be decreased to 25-33% of the usual dose it is best not to use these two drugs together. Adverse effects resulting from coadministration of azathioprine with other myelosuppres-sive agents or angiotensin-converting enzyme inhibitors include leukopenia, thrombocytopenia, and anemia as a result of myelosuppression. 

The classic antimetabolite azathioprine (AZA) is added to the other immunosuppressive drugs with a daily dosage of 1.5-2 mg/kg and has to be adjusted according to the white blood cell (WBC) count. Because of its myelosuppressive potential it has to be reduced when leucopenia occurs (fewer then 4,000 WBC/mm ). 

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