The impact of thiopurine-S-methyltransferase genotype on the adverse drug reactions to azathioprine in patients with inflammatory bowel diseases.

Abstract

BACKGROUND AND AIMS:

The thiopurine drugs, azathioprine (AZA) and 6-mercaptopurine, are established in the treatment of inflammatory bowel diseases (IBD). Polymorphisms in thiopurine S-methyltransferase (TPMT) gene have been associated with adverse drug reactions (ADRs) to AZA.

METHODS:

The aim of this study was to evaluate TPMT polymorphisms and AZA-related toxicity in a Slovak cohort of 220 IBD patients treated with AZA. In every patient, the dose and duration of AZA therapy, concomitant 5-aminosalicylate (5-ASA) medication, frequency, type, time to onset, dose of ADR and concomitant 5-ASA at the onset of ADR were recorded. Each patient was also genotyped for the presence of variant TPMT alleles (*2,*3A,*3B,*3C). Frequency, type and circumstances of ADRs were compared according to TPMT status.

RESULTS:

Of the 220 patients, 205 (93.2 %) were wild-type (TPMT*1/*1), one (0.5%) carried a TPMT*1/*3C allele, 13 (5.9 %) carried TPMT *1/*3A allele and one was homozygous for TMPT *3A allele. No TPMT *2 mutation was found. The incidence of adverse drug reactions was 62/205 (30.2 %) in the wild-type group as compared to 13/15 (86.7 %) in the TPMT mutation group, p=2.10-5. Leukopenia (WBC< 3.0*10^9/L) occurred in 21/205 (10.2 %) patients with wild type TPMT versus 11/15 (73.3 %) patients with TPMT mutations, p=0.000001. There was no significant difference between TMPT groups in gastrointestinal or other ADRs. No impact of 5-ASA on the incidence and severity of AZA adverse drug reactions was observed.

CONCLUSION:

The incidence of leukopenia in TPMT mutant patients was significantly higher and more severe as compared to TPMT wild type patients. We observed no impact of concomitant 5-ASA therapy on AZA induced toxicity (Tab. 4, Fig. 2, Ref. 37).

• Authors: T Hlavaty, M Batovsky, D Balakova, I Pav, P Celec, M Gregus, M Zakuciova, M Hlista, M Horakova, B Desatova, T Koller, J Toth, L Kadasi, M Huorka, Slovak IBD study group (SK IBD)
• Journal: Bratislavske lekarske listy (Bratisl Lek Listy) Vol. 114 Issue 4 Pg. 199-205 ( 2013) ISSN: 0006-9248 [Print] Slovakia
• PMID: 23514552 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Immunosuppressive Agents
• Methyltransferases
• thiopurine methyltransferase
• Azathioprine

Topics

• Adult
• Azathioprine (adverse effects, therapeutic use)
• Female
• Genotype
• Humans
• Immunosuppressive Agents (adverse effects, therapeutic use)
• Inflammatory Bowel Diseases (drug therapy, genetics)
• Male
• Methyltransferases (genetics)
• Pharmacogenetics
• Polymorphism, Genetic