Azathioprine and mercaptopurine
Azathioprine and mercaptopurine (both thiopurines) are used as immune suppressants. They are used in a wide range of conditions including inflammatory bowel disease (IBD), rheumatoid arthritis, and renal transplant patients. Dose adjustment is required according to thiopurine methyltransferase (TPMT) enzyme activity status.
- To guide dose-adjustment towards optimal drug exposure in relation to drug efficacy and toxicity
- Therapeutic drug monitoring of thiopurine metabolites (6-methyl-mercaptopurine [6-MMP], and 6-thioguanine nucleotides [6-TGN]) is recommended routinely in IBD patients.
- Sometimes used in rheumatological and dermatological conditions, but there are less available data for these.
- Diagnosis
- Disease resistant to drug versus inadequate drug exposure (including uncertain adherence)
- Adverse drug reaction versus underlying disease
- Note: Clinicians are encouraged to consider additional gauges of drug effects dependent upon the clinical presentation, and other blood test results (see below).
Assay details
See Canterbury Health Labs 6-TGN and 6-MMP assay information.
Timing of concentration sample collection
- Blood samples for metabolite monitoring can be taken at any time in relation to the dose because of the long half-lives of the metabolites.
- Where 6-TGN and 6-MMP are being measured concurrently, a single EDTA (lavender top) sample is sufficient.
- Concentrations of 6-TGN and 6-MMP should be checked 4 weeks after starting the drug or changing the dose, i.e. at steady-state. After therapeutic concentrations are achieved, re-checking of the metabolite concentrations may not be required unless the clinical situation changes but some authors recommend checking concentrations regularly (e.g. annually).
- The turnaround of thiopurine metabolite concentrations is up to 7 days.
Other monitoring
- TPMT (thiopurine methyltransferase) is a key enzyme in the metabolism of thiopurines. TPMT polymorphisms result in large differences in 6-TGN and 6-MMP concentrations, which can be life-threatening, so it is important to measure TPMT enzyme activity before initiating thiopurine therapy.
- Full blood count and liver function tests should be monitored weekly for 4 weeks after initiation of thiopurine therapy, then monthly for 3 months, and then once every 3 months thereafter.
Reference Range
| 6-TGN | 6-MMP | |
| Canterbury Health Labs reference range | 235–450 pmol/8 x108 RBC* | < 5,700 pmol/8 x108 RBC |
| Under-dosing or poor compliance | < 200 pmol/8 x108 RBC | Low/absent |
| Thiopurine resistance (6-MMP:6-TGN ratio > 20) |
< 200 pmol/8 x108 RBC | > 4,000 pmol/8 x108 RBC |
| Adequate dosing | 235–450 pmol/8 x108 RBC | < 5,700 pmol/8 x108 RBC |
| Thiopurine-refractory disease | > 235 pmol/8 x108 RBC | < 5,700 pmol/8 x108 RBC |
| Potential Toxicity | > 450 pmol/8 x108 RBC | > 5,700 pmol/8 x108 RBC |
| *The therapeutic range for 6-TGN during thioguanine treatment (another thiopurine drug) is different (800–1,200 pmol/8 x108 RBC) | ||
Factors affecting interpretation
Factors that may give a false assay result
Recent blood transfusion, or uraemia can give a false TPMT enzyme activity result.
Dose individualisation and adjustment
- Initially, use the lower end of the dose range (especially for elderly patients, and patients with hepatic impairment [e.g. advanced age, alcoholic liver disease] or renal impairment [eGFR < 20 mL/min]).
- In adult patients with normal TPMT enzyme activity, the usual starting target dose of azathioprine is 2-3 mg/kg/day. For 6-mercaptopurine this is 1-1.5mg/kg/day. Further guidance in available in Community HealthPathways.
- Thiopurine metabolite concentrations increase in proportion to the azathioprine dose (except for those with thiopurine resistance as determined by 6-TGN/6-MMP ratio as above).
- Adjust the dose according to:
- Metabolite concentrations.
- TPMT status:
- Heterozygous for an inactivating TPMT allele: Start at 33–50% of the starting target dose.
- Homozygous for inactivating TPMT alleles: Start at less than 10% of starting target dose.
- Dose adjustment may result in dosing outside of that which is Medsafe-approved
Contacts for help with interpretation
Medicines Information ph: 03 364 0900 or email medicines.information@cdhb.health.nz
Warner B, Johnston E, Arenas-Hernandez M, et al. A practical guide to thiopurine prescribing and monitoring in IBD. Frontline Gastroenterol. 2018;9:10-15
Khan A, Berahmana AB, Day AS, Barclay ML, Schultz M. New Zealand Society of Gastroenterology Guidelines on Therapeutic Drug Monitoring in Inflammatory Bowel Disease. N Z Med J. 2019;8:46-62
Gearry RB, Barclay ML, Roberts RL, et al. Thiopurine methyltransferase and 6-thioguanine nucleotide measurement: early experience of use in clinical practice. Intern Med J. 2005;35:580-5
Azathioprine: Drug information. Lexicomp®. Accessed 17/08/2023.
Thiopurine Dosing Guideline in Immunosuppressive Therapy. The Pink Book.
Last updated
March 2024