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Eur J Clin Pharmacol. 2009 May;65(5):533-40. doi: 10.1007/s00228-009-0630-y. Epub 2009 Feb 20.

TPMT but not ITPA gene polymorphism influences the risk of azathioprine intolerance in renal transplant recipients.

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1
Department of Pharmacology, Pomeranian Medical University, Powstancow Wlkp. 72, Szczecin 70-111, Poland. mkurz@op.pl

Abstract

PURPOSE:

Thiopurine drugs have to be withdrawn in 10-30% of cases due to side effects, and it has been presented that genetic factors may be responsible for some of reported toxicity cases. Among polymorphic enzymes of thiopurines' metabolic pathway, thiopurine S-methyltransferase (TPMT) has been studied most extensively, and some recent studies point to inosine triphosphate pyrophosphohydrolase (ITPA) polymorphism as an additional toxicity risk factor.

METHODS:

The aim of the current study was to evaluate an association between TPMT and ITPA gene polymorphisms and drug intolerance in a cohort of 157 renal transplant recipients treated with azathioprine (AZA). Each subject was genotyped for the presence of variant TPMT (*2, *3A, *3B, and *3C) and ITPA (94C>A and IVS2+21A>C) alleles.

RESULTS:

Mean AZA dose, mean white-blood-cell count, and platelet count in the course of treatment were lower in carriers of variant TPMT alleles compared to patients with TPMT wild-type genotype. Leukocyte numbers fell below 4.0 x 10(9)/L in 41.2% of TPMT heterozygous renal transplant recipients, compared to only 18.0% of wild-type patients (P < 0.01). In contrast, ITPA genotype did not influence AZA dose, hematological parameters, or leucopenia risk.

CONCLUSIONS:

Our results suggest that routine genotyping of renal transplant recipients for TPMT variants may be useful in reducing the risk of AZA-related myelotoxicity, but there is not enough evidence to introduce ITPA testing into clinical practice.

PMID:
19229528
DOI:
10.1007/s00228-009-0630-y
[Indexed for MEDLINE]
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