The effects of AZA/6-MP are mediated via the drug’s intracellular conversion to thiopurine nucleotide metabolites, which are incorporated into cellular nucleic acids, a process which leads to inhibition of de novo purine synthesis. As shown in Figure 1, AZA is rapidly converted to 6-MP via nonenzymatic processes, after which 6-MP may be catabo-lized to the inactive metabolite, 6-methylmercaptopurine (6-MMP), or anabolized to the active metabolites, 6-thioguanine nucleotides (6-TG) and 6-MMP ribonucleotides, via competing pathways. The methylation of 6-MP to 6-MMP ribonucleotides is catalyzed by thiopurine methyltransferase (TPMT).
Wide individual differences in TPMT activity have been observed; the differences are largely due to a common genetic polymorphism . The frequency distribution of TPMT activity is trimodal: one in 300 individuals have low or absent enzyme activity, approximately 11% have intermediate activity, and approximately 89% have normal to high enzyme activity. Enzyme activity is expressed in a Mendelian fashion: a single genetic locus with two alleles, TPMTL for low activity and TPMTH for high activity, thereby producing the trimodal distribution. Studies have shown that the variable expression of TPMT contributes to the myelotoxicity seen with AZA use , and that low TPMT status may warn of early bone marrow toxicity, especially within the first four months after the initiation of purine analogue treatment . As a result of the competitive pathways setup, a reciprocal relationship exists between TPMT activity and the formation of cytotoxic 6-TG nucleotide metabolites.
Figure 1) Azathioprine drug metabolism. HPRT Hypoxanthine phosphoribosyl transferase; TPMT Thiopurine methyltransferase; XO Xanthine oxidase