PURINE ANALOGS: AZATHIOPRINE &
6-mercaptopurine (6-MP) are purine anti-metabolites that have immunosuppressive
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.
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.
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.
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.
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.