Mechanism of action and metabolism of AZA
AZA is a prodrug converted to 6-MP, which is then converted to thiopurine nucleotides (6-TGN), which decrease de novo synthesis of purine nucleotides with resultant inhibition of DNA, RNA, and protein synthesis. This results in both cytotoxicity and decreased cellular proliferation. 6-TGN metabolite levels can be measured within 4 hours of taking AZA with 230 to 400 pmole/8 × 10 8 red blood cells being therapeutic (cost: $270).
The metabolism of 6-MP by two enzymes—XO and TPMT—results in the formation of inactive metabolites. Inhibition of XO (by allopurinol, febuxostat) or TPMT (by sulfasalazine) causes an accumulation of 6-MP resulting in toxicity. In addition, TPMT enzyme activity is affected by genetic polymorphisms with 90% having high activity, 10% intermediate activity, and 0.3% low activity. Blacks have 17% less TPMT activity than whites. Patients with low TPMT activity are at risk for the sudden onset of severe myelosuppression occurring between 4 and 10 weeks after starting AZA. Patients with intermediate activity have more frequent adverse side effects, particularly gastrointestinal (GI). TPMT genotype and phenotype can be measured. Notably, the TPMT enzyme activity (i.e., phenotype) cannot always be predicted by the genotype. Whether or not this is necessary prior to starting AZA is controversial since over half of all cases of leukopenia are seen in patients with normal TPMT activity