Azathioprine Metabolites, whole blood

Azathioprine, which is a pro drug of 6-mercaptopurine (6-MP), is considered an effective immunosuppressive treatment of inflammatory bowel disease, particularly in patients with steroid resistant disease. However, the use of azathioprine is limited by both its long onset of action (three to four months) and drug toxicities, which include hepatotoxicity, bone marrow suppression, pancreatitis, and allergic reactions. Long term drug use has been associated with neoplasia. 

Azathioprine is converted to 6-mercaptopurine in vivo, where it is subsequently metabolized into two active metabolites; either 6-thioguanine nucleotides (6-TG) by the enzyme IMPDH, or to 6-methyl-mercaptopurine ribonucleotides (6-MMRP) by the enzyme thiopurine methyltransferase TPMT. 6-TG is considered cytotoxic and thus, is associated with bone marrow suppression, while 6-MMRP is associated with hepatotoxicity. In population studies, the activity of the enzyme TPMT has been shown to be trimodal with 90 per cent of subjects having high activity, 10 per cent intermediate activity, and 0.3 per cent with low or no activity. This variation in TPMT activity has been related to three distinct TPMT mutations and has permitted the development of TPMT genotyping based on a polymerase chain reaction (PCR). Genetic analysis has been explored as a technique to proactively identify patients at risk for bone marrow suppression. Those with high TPMT activity may be started at a higher initial dose of therapy, while those with low TPMT activity may not be good candidates for azathioprine therapy.