European Journal of Clinical Pharmacology

, Volume 59, Issue 11, pp 797–801

Thiopurine methyltransferase (TPMT) genotype distribution in azathioprine-tolerant and -intolerant patients with various disorders. The impact of TPMT genotyping in predicting toxicity

  • Lene O. Reuther
  • Ben Vainer
  • Jesper Sonne
  • Niels-Erik Larsen

DOI: 10.1007/s00228-003-0698-8

Cite this article as:
Reuther, L.O., Vainer, B., Sonne, J. et al. Eur J Clin Pharmacol (2004) 59: 797. doi:10.1007/s00228-003-0698-8



To study the distribution of the thiopurine methyltransferase (TPMT) genotype among azathioprine (Aza)-tolerant and -intolerant patients with various disorders, and to investigate a possible relationship with the Aza metabolite levels.


Forty-six Aza-tolerant and six Aza-intolerant patients had the TPMT genotype distribution determined using a polymerase chain reaction (PCR) assay and the forty-six Aza-tolerant patients had the Aza metabolite levels determined using a high-pressure liquid chromatography (HPLC) analysis.


One non-functional TPMT mutant allele was demonstrated in 2 of the 46 Aza-tolerant patients (4.4%) and one or two non-functional mutant alleles in 2 of the 6 Aza-intolerant patients (33.3%). Of the 4 patients, with one or two non-functional mutant alleles 2 (50%) were intolerant to Aza compared with 4 of the 48 patients (8.3%) with no mutations detected. The time to hepatotoxicity did not differ significantly between the 2 patients with one or two non-functional mutant alleles and the remaining 3 patients (P=0.5). The TPMT genotype distribution differed slightly in the three different categories of disorders (P=0.05). The median E-6-TGN level among the 2 TPMT heterozygous patients was 275 pmol/8×108 RBC (range 240–310), whereas the remaining 44 patients had a median E-6-TGN level of 110 pmol/8×108 RBC (range 0–440) (P=0.07).


Although TPMT genotyping cannot be recommended on behalf of the present study, it is to be expected that half of the patients with one or two non-functional TPMT mutant alleles will develop Aza intolerance leading to withdrawal of therapy. Thus, clinicians may anticipate about 5% of the patients to develop intolerance to Aza therapy solely for that reason.


Azathioprine Intolerance Thiopurine methyltransferase 

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Lene O. Reuther
    • 1
  • Ben Vainer
    • 2
  • Jesper Sonne
    • 1
  • Niels-Erik Larsen
    • 3
  1. 1.Department of Clinical PharmacologyGentofte University HospitalHellerupDenmark
  2. 2.Department of GastroenterologyGlostrup University HospitalDenmark
  3. 3.Clinical Pharmacological LaboratoryGlostrup University HospitalDenmark

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