title: Augmenting clinical interpretability of thiopurine methyltransferase laboratory evaluation.
abstract: OBJECTIVE
  Individuals with decreased thiopurine methyltransferase (TPMT) activity are at risk of adverse effects of thiopurine administration whereas its increased activity may inactivate drugs faster. We evaluated genotype-phenotype correlations in patients with suspected hematological malignancies and inflammatory bowel disease from our region based on findings of nonlinear TPMT enzyme kinetics previously unreported.
  
  
  METHODS
  The study group comprised 267 individuals. They were screened for the most common variants of low TPMT activity. TPMT activity was measured in erythrocytes using the HPLC rate-blanked method.
  
  
  RESULTS
  Thirty-three patients (12.4%) were heterozygous (26 were TPMT*1/*3A, 5 TPMT*1/*2, 2 TPMT *1/*3C) and 1 was a compound heterozygote (*2/*3A). Normal and low normal TPMT activities substantially overlapped in wild-type and heterozygous individuals, whereas high activities were found in 29 wild-type genotyped patients. Extreme and life-threatening toxicity was observed in the compound heterozygote patient.
  
  
  CONCLUSIONS
  Activity measurement performed at diagnosis provides clinicians with information on immediate pharmacokinetic-related adverse events and/or hypermetabolism, and genotyping may indicate the rate of pharmacodynamic thioguanine nucleotide accumulation due to slower overall thiopurine metabolism.
authors.affiliation: Department of Pharmacology, Masaryk University School of Medicine, Brno, Czech Republic.
authors.forename: Regina
authors.initials: R
authors.lastname: Demlova
authors.forename: Martina
authors.initials: M
authors.lastname: Mrkvicova
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Sterba
authors.forename: Hana
authors.initials: H
authors.lastname: Bernatikova
authors.forename: Jan
authors.initials: J
authors.lastname: Stary
authors.forename: Martina
authors.initials: M
authors.lastname: Sukova
authors.forename: Alena
authors.initials: A
authors.lastname: Mikuskova
authors.forename: Alica
authors.initials: A
authors.lastname: Chocholova
authors.forename: Beata
authors.initials: B
authors.lastname: Mladosievicova
authors.forename: Andrea
authors.initials: A
authors.lastname: Soltysova
authors.forename: Darina
authors.initials: D
authors.lastname: Behulova
authors.forename: Katerina
authors.initials: K
authors.lastname: Pilatova
authors.forename: Lenka
authors.initials: L
authors.lastname: Zdrazilova-Dubska
authors.forename: Dalibor
authors.initials: D
authors.lastname: Valik
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001215:Asparaginase / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D003520:Cyclophosphamide / Q000627:therapeutic use; D003561:Cytarabine / Q000627:therapeutic use; D018153:Czech Republic; D003630:Daunorubicin / Q000627:therapeutic use; D004910:Erythrocyte Membrane / Q000201:enzymology; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000097:blood; D008297:Male; D015122:Mercaptopurine / Q000627:therapeutic use; D008727:Methotrexate / Q000627:therapeutic use; D008780:Methyltransferases / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics; D011241:Prednisone / Q000627:therapeutic use; D018154:Slovakia; D014750:Vincristine / Q000627:therapeutic use
chemical_list: D003561:Cytarabine; D014750:Vincristine; D003520:Cyclophosphamide; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001215:Asparaginase; D011241:Prednisone; D008727:Methotrexate; D003630:Daunorubicin