Thiopurine Metabolism and Toxicity

Thiopurine drugs such as 6-mercaptopurine (6-MP), azathioprine (AZA), and 6-thioguanine (6-TG) are used as both chemotherapeutic agents to treat leukemias

Thiopurine Metabolism and Toxicity 545

and immunosuppressive agents to treat inflammatory bowel disease, rheumatic and hematologic autoimmune diseases, and following solid organ transplant. Thiopurine drugs are inactive and require metabolism of the prodrug to thioguanine nucleotides (TGN) for cytotoxic and immunosuppressive action. TGNs are formed after a series of enzymes modify the prodrug (Fig. 74.1) beginning with hypoxanthine guanine phos-phoribosyl transferase (HGPRT). While the exact mechanism of the effects of these drugs is unknown, theories include TGN incorporation into and interference with DNA and RNA synthesis and chromosomal replication, inhibition of T and B cell proliferation, and interference with natural-killer (NK) cell cytotoxicity.4'5

There is a delayed onset of therapeutic action of the thiopurines (about 17 weeks in Crohn's disease patients), and the clinical response rate varies among different

Thiopurine Metabolites And Toxicity

Figure 74.1 Metabolism of azathioprine and 6-mercaptopurine. A series of competing enzymatic pathways result in formation of either inactive metabolites or hepato or myelotoxic metabolites (TPMT—thiopurine methyltransferase; XO—xanthine oxidase, HGPRT—hypoxanthine guanine phosphoribosyltransferase; IMPDH—inosine monophosphate dehydrogenase; GMPS—guanine monophosphate synthase).

Figure 74.1 Metabolism of azathioprine and 6-mercaptopurine. A series of competing enzymatic pathways result in formation of either inactive metabolites or hepato or myelotoxic metabolites (TPMT—thiopurine methyltransferase; XO—xanthine oxidase, HGPRT—hypoxanthine guanine phosphoribosyltransferase; IMPDH—inosine monophosphate dehydrogenase; GMPS—guanine monophosphate synthase).

diseases. Side effects of the thiopurines include allergic reactions, nausea, acute pancreatitis, bone marrow suppression, hepatotoxicity, and infections. Thiopurine toxicity leading to withdrawal of patients from the drug occurs in 10-28% of patients.5,6 Symptoms of severe and potentially life-threatening bone marrow suppression, affecting about 1.4-5% of patients, usually occur within the first 30 days.5 Patients with a deficiency of thiopurine S-methyltransferase enzyme (TPMT) activity are particularly at risk.

Supplements For Diabetics

Supplements For Diabetics

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