Metabolism of 6-mercaptopurine (6-MP) and azathioprine (AZA) is complex. Azathioprine is a prodrug that is non-enzymatically converted to 6-MP. 6-MP is then either inactivated by thiopurine methyltransferase (TPMT) to 6-methylmercaptopurine or by xanthine oxidase to 6-thiouric acid, or it is activated via a multistep enzymatic pathway to the putative active metabolites, the 6 thioguanine nucleotides (6-TGN).1 The enzyme activity of TPMT is genetically determined. There is a trimodal distribution of TPMT activity in the general population: homozygous low activity occurs at a frequency of 0.3%; heterozygous or intermediate activity occurs at a frequency of 11%; and homozygous high or normal activity occurs at a frequency of 89%.2 At least 10 variant alleles for TPMT have been associated with decreased enzyme activity (*2, *3A, *3B, *3C, *3D, *4, *5, *6, *7, *10). Patients with low or intermediate TPMT enzyme activity shunt 6-MP away from the 6-methylmercaptopurine metabolite and towards 6-TGN. Excess concentrations of 6-TGN have been associated with leucopenia. The practical application of these clinical pharmacology discoveries and the results of randomised controlled trials in patients with inflammatory bowel disease (IBD) who require treatment with AZA or 6-MP are reviewed below.

The first question that clinicians must ask is which drug to use? There is virtually no published information regarding the relative immunosuppressive properties of AZA or 6-MP. Clinical experience suggests that they are equivalent if the doses are adjusted for differences in the content of 6-MP. Approximately 88% of AZA is converted to 6-MP. Azathioprine is 55% 6-MP by molecular weight. Thus a conversion factor of 2.08 will convert a dose of …