Pharmacology and Mechanism of Action

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Azathioprine (AZA) is an immunosuppressive agent that is widely used in inflammatory rheumatic diseases, including RA, where there is evidence to support its role in suppression of disease activity (57). A typical dose for RA is 1 mg/kg/day increasing after four to six weeks to 2-3 mg/day. AZA is a prodrug, which is converted after absorption to the active agent, 6-mercaptopurine (6-MP). This is then converted by hypoxanthine-guanine phosporibosyl transferase (HGPRT) to 6-thioguanine nucleotides (6-TGNs). These play a major role in the development of cytotoxicity when incorporated into DNA and RNA (58). Two enzymes compete with HGPRT to reduce the intracellular levels of 6-TGNs. The first, xanthine oxidase, results in the formation of thiouric acid. This is an important route for the inactivation of 6-MP, and the xanthine oxidase inhibitor allopurinol significantly increases the risk of toxicity of AZA (59). Xanthine oxidase

Azathiprine Allopuyrinol

Figure 3 The metabolic pathway involved in the detoxification of azathioprine/6-MP. TPMT is a key enzyme (gray boxes) in which polymorphic variability can result in an increased risk of azathioprine toxicity. Abbreviations: HGPRT, hypoxanthine guanine phosphoribosyltransferase; MP, mercaptopurine; TPMT, thiopurine methyltransferase.

Figure 3 The metabolic pathway involved in the detoxification of azathioprine/6-MP. TPMT is a key enzyme (gray boxes) in which polymorphic variability can result in an increased risk of azathioprine toxicity. Abbreviations: HGPRT, hypoxanthine guanine phosphoribosyltransferase; MP, mercaptopurine; TPMT, thiopurine methyltransferase.

levels, however, do not appear to vary greatly between individuals. The second enzyme involved in 6-MP clearance is thiopurine methyltransferase (TPMT). TPMT inactivates 6-MP through the formation of methyl mercaptopurine (58) (Fig. 3).

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