Clinical use and practical application of TPMT enzyme and 6-mercaptopurine metabolite monitoring in IBD.
6-mercaptopurine (6-MP) and its parent drug azathioprine (AZA) have been proven to be effective for both steroid-dependent and chronically active, or steroid-resistant inflammatory bowel disease, as well as for the prevention of relapse. Concerns about toxicity, delayed onset of action, and therapeutic failure (1 out of 3 patients) have restricted their use. Recent pharmacogenetic advances have led to the development of novel strategies to optimize and individualize therapy with AZA and 6-MP, maximizing efficacy while minimizing toxicity. We have defined a range of optimal therapeutic 6-MP metabolite levels, as well as an association of metabolite levels with medication-induced toxicity and the genotype of the main catabolic enzyme, thiopurine methyltransferase (TPMT). Measurement of 6-MP metabolite levels and TPMT molecular analysis provide clinicians with useful tools for optimizing therapeutic response to 6-MP/AZA, as well as for identifying individuals at increased risk for drug-induced toxicity.
Seidman
Ernest G
EG
Division of Gastroenterology, Hepatology, and Nutrition, Faculty of Medicine, University of Montreal, Montreal, Canada.
D000963:Antimetabolites / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D001379:Azathioprine / Q000009:adverse effects / Q000627:therapeutic use*; D019317:Evidence-Based Medicine; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000378:metabolism*; D008099:Liver / Q000187:drug effects; D015122:Mercaptopurine / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D012074:Remission Induction
D000963:Antimetabolites; D007166:Immunosuppressive Agents; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine