PMID- 21544018
OWN - NLM
STAT- MEDLINE
DCOM- 20110914
LR  - 20220330
IS  - 1536-3694 (Electronic)
IS  - 0163-4356 (Linking)
VI  - 33
IP  - 3
DP  - 2011 Jun
TI  - Association between adverse effects under azathioprine therapy and inosine 
      triphosphate pyrophosphatase activity in patients with chronic inflammatory bowel 
      disease.
PG  - 321-8
LID - 10.1097/FTD.0b013e31821a7c34 [doi]
AB  - 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 aminotransferase, 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 
      mumol/(gHb.h) [hemoglobin (Hb)]. Decreased ITPA activities [particularly <89.2 
      mumol/(gHb.h)] were frequently accompanied by leucopenias, whereas very low enzyme 
      activities [<37.3 mumol/(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.
FAU - Shipkova, Maria
AU  - Shipkova M
AD  - Central Institute for Clinical Chemistry and Laboratory Medicine, Department of 
      Internal Medicine, Gastroenterology, Hepatology, and Oncology, Klinikum 
      Stuttgart, Germany. m.shipkova@klinikum-stuttgart.de
FAU - Franz, Jutta
AU  - Franz J
FAU - Abe, Manabu
AU  - Abe M
FAU - Klett, Corinne
AU  - Klett C
FAU - Wieland, Eberhard
AU  - Wieland E
FAU - Andus, Tilo
AU  - Andus T
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Ther Drug Monit
JT  - Therapeutic drug monitoring
JID - 7909660
RN  - EC 3.6.1.- (Pyrophosphatases)
RN  - EC 3.6.1.9 (ITPA protein, human)
RN  - MRK240IY2L (Azathioprine)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Azathioprine/*adverse effects/therapeutic use
MH  - Female
MH  - Genotype
MH  - Heterozygote
MH  - Homozygote
MH  - Humans
MH  - Inflammatory Bowel Diseases/drug therapy/*enzymology/genetics/metabolism
MH  - Male
MH  - Middle Aged
MH  - Mutation
MH  - Phenotype
MH  - Polymorphism, Genetic
MH  - Pyrophosphatases/genetics/*metabolism
MH  - Young Adult
EDAT- 2011/05/06 06:00
MHDA- 2011/09/15 06:00
CRDT- 2011/05/06 06:00
PHST- 2011/05/06 06:00 [entrez]
PHST- 2011/05/06 06:00 [pubmed]
PHST- 2011/09/15 06:00 [medline]
AID - 10.1097/FTD.0b013e31821a7c34 [doi]
PST - ppublish
SO  - Ther Drug Monit. 2011 Jun;33(3):321-8. doi: 10.1097/FTD.0b013e31821a7c34.