Journal
THERAPEUTIC DRUG MONITORING
Volume 33, Issue 3, Pages 321-328Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/FTD.0b013e31821a7c34
Keywords
inosine triphosphate pyrophosphatase; chronic inflammatory bowel disease; phenotype; genotype; drug toxicity; therapeutic drug monitoring
Funding
- National Institutes of Health
- Welcome Trust
- Howard Hughes Medical Institute
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Background: Inosine triphosphate pyrophosphatase (ITPA) catalyzes the pyrophosphohydrolysis of inosine triphosphate to inosine monophosphate. Recently, single-nucleotide polymorphisms in the ITPA gene, associated with decreased enzyme activity, have been reported. Some clinical studies have demonstrated that the 94C>A mutation is linked to flu-like symptoms, rash, and pancreatitis during azathioprine (AZA) therapy and to early AZA discontinuation. In this study, we investigated whether the enzyme phenotype is also related to adverse effects (AEs). Methods: Patients suffering from inflammatory bowel disease who were treated with AZA (N = 160; age 43 +/- 12 years) were included. Data were categorized into quartiles according to the ITPA activity. Information about the therapeutic regimen, AEs [leucopenia, increased hepatic enzymes (alanine aminotransferase, aspartate aminotrasnferase, gamma-glutamyl transferase), flu-like symptoms, and pancreatitis], cotherapy, and comorbidity was obtained from the responsible clinicians and patients by using a standardized questionnaire. ITPA activity was measured by a validated high-performance liquid chromatography procedure. In patients with decreased ITPA activity, the 94C>A and IVS2 + 21A>C genotypes were determined. Results: AEs were reported significantly more often for patients with low ITPA activity than for patients with high ITPA activity; the highest odds ratio for occurrence of AEs was found to be below a threshold of 59.9 mu mol/(gHb.h) [hemoglobin (Hb)]. Decreased ITPA activities [particularly <89.2 mu mol/(gHb.h)] were frequently accompanied by leucopenias, whereas very low enzyme activities [<37.3 mu mol/(gHb.h)] were associated with a higher incidence of increased liver enzymes. Conclusions: The results demonstrate a relationship between low ITPA activity and AEs and support the idea that the determination of ITPA phenotype might be an appropriate alternative to genotyping.
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