Azathioprine ADME

1. Incorporation of 6-thioguanosine triphosphate (6TGTP) into RNA

2. Incorporation of 6-thiodeoxyguanosine triphosphate (6TdGTP) into DNA

3. Inhibition of de novo purine synthesis by methylmercaptopurine nucleotides such as methylthioinosine monophosphate (meTIMP)

4. Inhibition of RAC1 by 6TGTP which induces apoptosis in activated T-cells.

While AZA has been supplanted as an antitumour drug, it remains useful as an immunosuppressant antimetabolite drug indicated to treat rheumatoid arthritis, Crohn's disease, ulcerative colitis, cancer and to prevent rejection in kidney transplant patients.

The molecular steps of AZA metabolism are described in this pathway. Briefly, oral AZA is rapidly converted to 6MP. Initial 6MP metabolism occurs along competing catabolic (XDH, TPMT) and anabolic (HPRT) enzymatic pathways. Once formed, 6-thiosine 5′-monophosphate (6TIMP) is further metabolized by inosine monophosphate dehydrogenase (IMPDH) and guanosine monophosphate synthetase (GMPS) to 6-thioguanosine 5′monophosphate (6TGMP). 6TGMP is then converted to the pharmacologically-active di- and tri- derivatives by their respective kinases.