Azathioprine (AZA) and 6-mercaptopurine (6-MP) are frequently used in the treatment of inflammatory bowel disease (IBD). However, about 10–20% of IBD-patients are unable to tolerate AZA and/or 6-MP due to side-effects. 6-Thioguanine (6-TG), the active metabolite of AZA and 6-MP, may be an alternative in these cases.
We measured 6-TG levels in erythrocytes 4 weeks after start of 6-TG therapy in nine out-patients with IBD. 6-TG concentrations were considered to reach steady state in 4 weeks having a half-life of approximately 5 days. The mean age of the patients was 41 years (range 24–59), three were male, six were female. Two patients were intolerant to 6-MP, 5 to AZA and two to both drugs. Five patients received a daily dose of 20 mg, four were given 40 mg. The results are summarized in Table 1.
Table 1.
Patient characteristics.
| Number | Sex | Age (years) | IBD | Intolerance | Dose (mg) | 6-TG (*) |
|---|---|---|---|---|---|---|
| 1 | M | 59 | UC | 6-MP | 20 | 552 (#) |
| 2 | M | 51 | UC | AZA | 20 | 270 (##) |
| 3 | F | 24 | CD | 6-MP | 20 | 1013 |
| 4 | F | 35 | CD | AZA | 20 | 819 |
| 5 | F | 46 | UC | AZA/6-MP | 20 | 1072 |
| 6 | F | 24 | CD | AZA | 40 | 986 |
| 7 | M | 44 | UC | AZA | 40 | 1359 |
| 8 | F | 51 | CD | AZA | 40 | 703 |
| 9 | F | 34 | CD | AZA/6-MP | 40 | 1666 |
6-TG concentrations at t = 4 weeks, at t = 2 weeks (#) and at t = 1 week (##) in pmol/8×108RBC.
UC = ulcerative colitis, CD = Crohn's disease.
Poor correlation was found between dose and 6-TG concentration (r : 0.34). 6-TG concentrations after 6-TG intake are relatively high compared with blood concentrations measured in AZA or 6-MP treated patients (mean: 276, range: 0–792) [1]. Beside drug efficacy 6-TG concentrations are also associated with bone marrow suppression, especially when these concentrations are high; Dubinsky et al. [1] measured a mean 6-TG concentration of 490 in a pediatric leukopenic population treated with AZA or 6-MP [2].
No leukopenia was observed in our 6-TG treated group.
One of our patients showed an early allergic reaction to 6-TG and developed high fever and erythema nodosum within the first week (patient 2). Another patient discontinued 6-TG after 3 weeks because of total malaise (patient 1). Late, pharmacological explainable adverse reactions due to high 6-TG concentrations did not occur in the 4 week period.
These results suggest that 6-TG may serve as a safe alternative in AZA and 6-MP intolerant IBD-patients. Frequent 6-TG concentration measurement and leukocyte counts are mandatory in determining optimal dose and guaranteeing safety. Further data are needed to establish safety and efficacy in the long term. We therefore initiated a prospective multicenter clinical trial.
References
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