No induction of thiopurine methyltransferase during thiopurine treatment in inflammatory bowel disease.
The aim of this study was to follow, during standardized initiation of thiopurine treatment, thiopurine methyltransferase (TPMT) gene expression and enzyme activity and thiopurine metabolite concentrations, and to study the role of TPMT and ITPA 94C > A polymorphisms for the development of adverse drug reactions. Sixty patients with ulcerative colitis or Crohn's disease were included in this open and prospective multi-center study. Thiopurine naïve patients were prescribed azathioprine (AZA), patients previously intolerant to AZA received 6-mercaptopurine (6-MP). The patients followed a predetermined dose escalation schedule, reaching target dose at Week 3; 2.5 and 1.25 mg/kg body weight for AZA and 6-MP, respectively. The patients were followed every week during Weeks 1-8 from baseline and then every 4 weeks until 20 weeks. TPMT activity and thiopurine metabolites were determined in erythrocytes, TPMT and ITPA genotypes, and TPMT gene expression were determined in whole blood. One homozygous TPMT-deficient patient was excluded. Five non compliant patients were withdrawn during the first weeks. Twenty-seven patients completed the study per protocol; 27 patients were withdrawn because of adverse events. Sixty-seven percent of the withdrawn patients tolerated thiopurines at a lower dose at Week 20. There was no difference in baseline TPMT enzyme activity between individuals completing the study and those withdrawn for adverse events (p = 0.45). A significant decrease in TPMT gene expression (TPMT/huCYC ratio, p = 0.02) was found, however TPMT enzyme activity did not change. TPMT heterozygous individuals had a lower probability of remaining in the study on the predetermined dose (p = 0.039). The ITPA 94C > A polymorphism was not predictive of adverse events (p = 0.35).
Lindqvist
M
M
Department of Medicine and Care, Division of Clinical Pharmacology, Faculty of Health Sciences, Linköping University, Linköping, Sweden. malin.lindqvist@imv.liu.se
Hindorf
U
U
Almer
S
S
Söderkvist
P
P
Ström
M
M
Hjortswang
H
H
Peterson
C
C
D000483:Alleles; D000963:Antimetabolites / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic; D005838:Genotype; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy*; D015122:Mercaptopurine / Q000494:pharmacology; D008780:Methyltransferases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D011687:Purines / Q000627:therapeutic use*; D011755:Pyrophosphatases / Q000235:genetics; D013997:Time Factors; D000097630:Inosine Triphosphatase
D000963:Antimetabolites; D015122:Mercaptopurine; D008780:Methyltransferases; D011687:Purines; D011755:Pyrophosphatases; C022745:thiopurine methyltransferase; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase