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- Title
Thiopurine methyltransferase (TPMT) genotype distribution in azathioprine-tolerant and -intolerant patients with various disorders. The impact of TPMT genotyping in predicting toxicity.
- Authors
Reuther, Lene O.; Vainer, Ben; Sonne, Jesper; Larsen, Niels-Erik
- Abstract
Objective. 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. Methods. 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. Results. 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). Conclusion. 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.
- Subjects
POLYMERASE chain reaction; HIGH performance liquid chromatography; GENETIC polymorphisms; CHROMATOGRAPHIC analysis; GENETIC research; HEPATOTOXICOLOGY
- Publication
European Journal of Clinical Pharmacology, 2004, Vol 59, Issue 11, p797
- ISSN
0031-6970
- Publication type
Article
- DOI
10.1007/s00228-003-0698-8