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CHaPtEr 87 Immunomodulating Pharmaceuticals 1179

metabolism by intestinal flora. In inflammatory arthritides, the imidazole moiety occurs rapidly within erythrocytes, both
sulfapyridine is likely to play a more important role, as it is rela- enzymatically by glutathione transferase and nonenzymatically.
tively well absorbed and has a bioavailability in the region of Several enzymes (Table 87.3) participate in the metabolism of
60%. Since acetylation is the principal route of metabolism of 6-mercaptopurine into active and inactive compounds. One of
sulfapyridine following absorption, acetylator status is a major these, thiopurine methyltransferase, is associated with genetic
determinant of the plasma half-life. For the same reason, slow polymorphisms; inherited changes in its activity may impact
acetylators are more liable to develop side effects. patient response to azathioprine. Xanthine oxidase inactivates
6-mercaptopurine by converting it to 6-thiouric acid. Since this
Mechanisms of Action for Sulfasalazine occurs mainly in the liver, toxicity from azathioprine therapy is
a danger in enzyme deficiency states, as a result of disease or
KEY CONCEPt use of drugs, such as allopurinol.
Sulfasalazine: Mechanism of Action Proposed Mechanisms of Action for Azathioprine
Suppresses the proliferation of lymphocytes The immunomodulatory mechanism of azathioprine remains
Suppresses proinflammatory cytokine production unclear. As purine analogues, the active metabolites interfere
Inhibits activation of nuclear factor (NF)-κB with the salvage pathway and de novo synthesis of purines, and
Promotes adenosine accumulation
they are incorporated into RNA and DNA. Proliferation of T
and B lymphocytes is inhibited, and function of natural killer
Sulfasalazine has a number of immunomodulatory effects. (NK) cells is suppressed without any change in cell numbers.
Lymphocyte proliferation is suppressed in vitro and involves The production of antibodies is also suppressed, although it is
both B-cell and T-cell populations. In vivo, a decrease in acti- not known which of these effects predominate in vivo. Cellular
vated lymphocytes in the peripheral blood is also seen. Tumor responses to chemoattractants are altered, and the production
necrosis factor-α (TNF-α) production is suppressed, and receptor of cytokines, such as interleukin-6 (IL-6), is also affected.
binding is inhibited. Sulfasalazine also inhibits activation of
the transcription factor, nuclear factor (NF)-κB. Like methotrexate, Adverse Effects
sulfasalazine inhibits AICAR transformylase and thus promotes Azathioprine is generally well tolerated. The most common side
accumulation of adenosine and its antiinflammatory actions via effects are mild and affect the GI system. Pancreatitis can occur
the adenosine A 2A receptor. Indeed, treatment of animals with as an idiosyncratic reaction. Hepatotoxicity and cholestasis are
an adenosine A 2A receptor antagonist reversed sulfasalazine’s not uncommon, and hepatic peliosis and nodular regenerative
reduction of leukocyte accumulation in an air-pouch model hyperplasia occur rarely. There have been reports of a possible
of inflammation. heightened risk for non-Hodgkin lymphoma, but because of
the rarity of these events, no definite link has been established
Adverse Effects between azathioprine and malignancies. Bone marrow suppression
In a large series, a quarter of those treated over 11 years stopped and opportunistic infections pose far greater threats.
6
treatment because of toxicity. Most toxicities occurred early
and were both trivial and resolved following therapy withdrawal. CYCLOPHOSPHAMIDE
Most common are nausea, vomiting, anorexia, and rash. Serious
cutaneous reactions, such as exfoliative dermatitis or Stevens- Alkylating agents were used in the treatment of inflammatory
Johnson syndrome, are rare. Transaminasemia and drug-induced diseases after promising reports on using nitrogen mustard in
hepatitis can occur. Blood dyscrasias with megaloblastic anemia, RA. Cyclophosphamide (Fig. 87.4) is metabolized to produce
neutropenia, aplastic anemia, and myelodysplastic syndrome the alkylating agent phosphoramide mustard as well as acrolein,
may arise. Neurological adverse effects include headache and which, although inactive, results in the hemorrhagic cystitis
dizziness or, more seriously, peripheral neuropathy, Guillain-Barré associated with cyclophosphamide. Cyclophosphamide can be
syndrome, or transverse myelitis. Sulfasalazine should be avoided given intravenously, but bioavailability following oral administra-
in patients with sulfa allergy, and glucose-6-phosphate dehydro- tion is high (>75%). Toxicity has severely limited its use in
genase (G6PD) deficiency screening should be performed before inflammatory diseases, although its contribution to the manage-
prescribing. ment of lupus nephritis cannot be denied. The alkylating actions
occur at guanine residues (principally on DNA but also on RNA)
AZATHIOPRINE resulting in cross-linkable strands and disruption of transcription
and translation.
Azathioprine, an imidazolyl derivative of 6-mercaptopurine (Fig.
87.3), has been widely used in RA and IBD as well as in solid
organ transplantations. Cleavage into 6-mercaptopurine and TABLE 87.3 Principal Enzymes Involved in
the Metabolism of azathioprine

Enzyme action
Azathioprine N
Glutathione transferase Cleaves azathioprine into 6-mercaptopurine
and imidazole moieties
H C N N NH Thiopurine Metabolism of 6-mercaptopurine
3
methyltransferase
N NO 2 N N Xanthine oxidase Conversion of 6-mercaptopurine to
6-thiouric acid
FIG 87.3 Azathioprine—chemical structure.