Pharmacology and Mechanism of Action

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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