The Pharmacology and Metabolism of the Thiopurine Drugs 6-Mercaptopurine and Azathioprine

Role of Aldehyde Oxidase and Xanthine Oxidase in the Metabolism of Purine-Related Drugs

“…One is thiol methylation, which is catalyzed by the enzyme thiopurine S-methyltransferase, to form the inactive metabolite methyl-6-mercaptopurine. The second route is thought to involve the initial oxidation of 6-MP to 8-oxo-6-MP followed by conversion to 6-thiouric acid (Elion, 1967;Van Scoik et al, 1985). However, Zimm et al, (1984) have identified 6-thioxanthine in the urine samples of some patients who received 6-MP by intravenous infusion which may indicate that 6-MP is converted to 6-thiouric acid via 6-thioxanthine.…”

“…In 1958, the immunosuppressive activity of 6-MP in rabbits was demonstrated by Schwartz et al (1958). Shortly, 6-(1-methyl-4-nitro-5-imidazolyl) thiopurine, AZT, was synthesized by the Hitchings-Elion laboratory and shown that this analogue of 6-MP acts as a pro-drug and is reduced non-enzymatically in body to 6-MP which is converted by sensitive neoplasms to the active form 6-thioinosinate by hypoxanthine-guanine phosphoribosyl-transferase (Van Scoik et al, 1985). AZT has a higher therapeutic index than 6-MP (Van Scoik et al, 1985).…”

“…AZT has more potent immunosuppressive effect than 6-MP and is preferred drug to prevent or delay graft rejection and treat rheumatoid arthritis (Chabner et al, 2001). 6-MP together with methotrexate are the drugs of choice in the treatment of childhood acute lymphocytic leukemia, especially in those cases where prolonged duration of remission is required (Knoester et al, 1993;Van Scoik et al, 1985); however, this thiopurine is not effective for the treatment of chronic lymphocytic leukemia, Hodgkings disease or other lymphomas/carcinomas (Rider, 2008).…”

“…6-MP, after administration, may enter into either anabolic or catabolic metabolic pathways (Lennard et al, 1991;Van Scoik et al, 1985). The anabolic pathway is responsible for conversion of 6-MP to its active form, whereas the drug is degraded to inactive forms in the catabolic pathway via two major inactivation routes (Fig.…”

“…Shortly, 6-(1-methyl-4-nitro-5-imidazolyl) thiopurine, AZT, was synthesized by the Hitchings-Elion laboratory and shown that this analogue of 6-MP acts as a pro-drug and is reduced non-enzymatically in body to 6-MP which is converted by sensitive neoplasms to the active form 6-thioinosinate by hypoxanthine-guanine phosphoribosyl-transferase (Van Scoik et al, 1985). AZT has a higher therapeutic index than 6-MP (Van Scoik et al, 1985). AZT has more potent immunosuppressive effect than 6-MP and is preferred drug to prevent or delay graft rejection and treat rheumatoid arthritis (Chabner et al, 2001).…”