-
Views
-
Cite
Cite
Filip Baert, Paul Rutgeerts, 6-Thioguanine: A Naked Bullet? (or How Pharmacogenomics Can Make Old Drugs Brand New), Inflammatory Bowel Diseases, Volume 7, Issue 3, 1 August 2001, Pages 190–191, https://doi.org/10.1097/00054725-200108000-00002
Close - Share Icon Share
Extract
6-Mercaptopurine (6-MP) and its prodrug azathioprine are the standard treatment for maintenance and remission induction of steroid-dependant and or fistulizing Crohn's disease (CD) and probably also refractory ulcerative colitis (UC). They act through inhibition of purine de novo synthesis by incorporation of 6-thioguanine (6-TG) metabolites into DNA. There are, however, limitations to the therapy. A significant number of patients do not respond even after adequate dosing (2–2.5 mg/kg for azathioprine and 1–1.5 mg/kg for 6-MP) and duration (4–6 months). Side effects will occur in 10–15% of patients depending on the dose used. Differences in bioavailability among different agents may occur (1). Some side effects are clearly idiosyncratic in nature, e.g., pancreatitis, fever, and rash, whereas other side effects are known to be dose dependent, including nausea, vomiting, liver toxicity, joint pains, and leucopenia.
In recent years, the main metabolites, rate-limiting enzymatic steps, and genetic polymorphisms involved in the metabolization of 6-MP have been described (2,3). It became clear that genetic polymorphisms in the activity of thiopurine methyltransferase (TPMT) accounted for a minority of the leucopenia episodes, especially those early on institution of the drug. 6-Thioguanine nucleotide (6-TGN) appeared to be the most important active metabolite, whereas 6-methylmercaptopurine ribonucleotide (6-MMPR) seemed to account for the dose-dependent hepatotoxicity (3,4).
