Azathioprine and 6-mercaptopurine (both thiopurines) are oral antimetabolite drugs used for their immune-suppressive properties. They are used in a wide range of clinical scenarios including inflammatory bowel disease (IBD), rheumatoid arthritis, and renal transplant patients.

 

Indications for measuring +

  • 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 alternative gauges of drug effects dependent upon the clinical presentation, and other blood test results (see below).

How to measure

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 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.

How to interpret

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.

Contacts for help with interpretation

Medicines Information ph: 03 364 0900

Key References

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

November 2023