Purine Analogs: Azathioprine & 6-Mercaptopurine

PURINE ANALOGS: AZATHIOPRINE & 6-MERCAPTOPURINE

Pharmacokinetics & Pharmacodynamics

Azathioprine and 6-mercaptopurine (6-MP) are purine anti-metabolites that have immunosuppressive properties.

The bioavailability of azathioprine (80%) is superior to 6-MP (50%). After absorption azathioprine is rapidly converted by a non-enzymatic process to 6-MP. 6-Mercaptopurine subsequently under-goes a complex biotransformation via competing catabolic enzymes (xanthine oxidase and thiopurine methyltransferase) that produce inactive metabolites and anabolic pathways that produce active thioguanine nucleotides. Azathioprine and 6-MP have a serum half-life of less than 2 hours; however, the active 6-thioguanine nucle-otides are concentrated in cells resulting in a prolonged half-life of days. The prolonged kinetics of 6-thioguanine nucleotide results in a median delay of 17 weeks before onset of therapeutic benefit from oral azathioprine or 6-MP is observed in patients with inflammatory bowel disease.

Clinical Uses

Azathioprine and 6-MP are important agents in the induction and maintenance of remission of ulcerative colitis and Crohn’s disease. Although the optimal dose is uncertain, most patients with normal thiopurine-S-methyltransferase (TPMT) activity  are treated with 6-MP, 1–1.5 mg/kg/d, or azathioprine, 2–2.5 mg/kg/d. After 3–6 months of treatment, 50–60% of patients with active disease achieve remission. These agents help maintain remission in up to 80% of patients. Among patients who depend on long-term glucocorticoid therapy to control active disease, purine analogs allow dose reduction or elimination of steroids in the majority.

Adverse Effects

Dose-related toxicities of azathioprine or 6-MP include nausea, vomiting, bone marrow depression (leading to leukopenia, macro-cytosis, anemia, or thrombocytopenia), and hepatic toxicity. Routine laboratory monitoring with complete blood count and liver function tests is required in all patients. Leukopenia or eleva-tions in liver chemistries usually respond to medication dose reduction. Severe leukopenia may predispose to opportunistic infections; leukopenia may respond to therapy with granulocyte stimulating factor. Catabolism of 6-MP by TPMT is low in 11% and absent in 0.3% of the population, leading to increased pro-duction of active 6-thioguanine metabolites and increased risk of bone marrow depression. TPMT levels can be measured before initiating therapy. These drugs should not be administered to patients with no TPMT activity and should be initiated at lower doses in patients with intermediate activity. Hypersensitivity reac-tions to azathioprine or 6-MP occur in 5% of patients. These include fever, rash, pancreatitis, diarrhea, and hepatitis.

As with transplant recipients receiving long-term 6-MP or azathioprine therapy, there appears to be an increased risk of lym-phoma among patients with inflammatory bowel disease. These drugs cross the placenta; however, there are many reports of suc-cessful pregnancies in women taking these agents, and the risk of teratogenicity appears to be small.

Drug Interactions

Allopurinol markedly reduces xanthine oxide catabolism of the purine analogs, potentially increasing active 6-thioguanine nucle-otides that may lead to severe leukopenia. Allopurinol should not be given to patients taking 6-MP or azathioprine except in care-fully monitored situations.