thiopurine

Thiopurines are a class of purine analog drugs that contain sulfur and are used as immunosuppressants and in cancer therapy. The two main agents in clinical use are azathioprine, a prodrug of 6-mercaptopurine (6-MP), and 6-mercaptopurine itself.

Pharmacology and mechanism of action: Thiopurines are converted inside cells to active metabolites, including thioinosinic acid and thioguanine nucleotides. These metabolites inhibit de novo purine synthesis and disrupt DNA replication, leading to suppressed proliferation of rapidly dividing cells, particularly T and B lymphocytes. The effects contribute to immunosuppression and antineoplastic activity.

Metabolism and pharmacogenetics: 6-MP metabolism is influenced by multiple enzymes. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) activates 6-MP to thioinosinic acid, while thiopurine S-m methyltransferase (TPMT) converts 6-MP to inactive methyl-6-MP metabolites. Xanthine oxidase also deactivates thiopurines. TPMT activity varies genetically; low or absent TPMT activity markedly increases the risk of bone marrow suppression. Variants in NUDT15 also affect thiopurine tolerance, particularly in some populations. Genetic testing for TPMT and, when available, NUDT15 can guide dosing to reduce toxicity.

Clinical use: Thiopurines are used to prevent organ transplant rejection and to treat inflammatory bowel diseases (Crohn’s disease and ulcerative colitis). They are also used in some autoimmune conditions and in certain leukemias, notably acute lymphoblastic leukemia, often as part of combination regimens.

Safety and monitoring: Common risks include bone marrow suppression, hepatotoxicity, pancreatitis, and cytopenias. Before starting therapy, and during treatment, regular complete blood counts and liver function tests are advised. Coadministration with allopurinol requires dose adjustment due to altered metabolism.