Determination of thiopurine methyltransferase genotype or phenotype optimizes initial dosing of azathioprine for the treatment of Crohn's disease.
BACKGROUND
although azathioprine (AZA) is an effective immunomodulator in treating Crohn's disease, some patients develop leukopenia and risk severe infections. Thiopurine methyltransferase (TPMT) is an enzyme responsible for the metabolism of AZA, and its activity is inversely related to the risk of developing acute leukopenia.


OBJECTIVE
the aim of this retrospective study is to determine whether initial AZA dosing based on TPMT genotype or phenotype alters the likelihood of developing acute leukopenia.


METHODS
between January 2000 and February 2001, 71 patients with Crohn's disease considered for AZA therapy and with a recorded TPMT genotype or phenotype were identified using a comprehensive text-oriented database at the University of Pittsburgh Medical Center, Presbyterian Hospital, Pittsburgh, PA. The baseline demographics, TPMT genotype or phenotype, initial dose of oral AZA, subsequent white blood counts, and complications that necessitated discontinuation of therapy were evaluated.


RESULTS
of the 63 patients with normal TPMT activity, 45 were started on 2 to 2.5 mg/kg/d of AZA, seven received doses less than 2 mg/kg/d, and 11 did not start AZA. Of the eight patients with intermediate TPMT activity, seven were started on 1 to 1.5 mg/kg/d of AZA, and one did not receive treatment. None of the patients that received AZA developed acute leukopenia (< 3,000/mm ).


CONCLUSIONS
patients with Crohn's disease and normal TPMT activity who were started on high-dose AZA (2-2.5mg /kg/d) and patients with intermediate enzyme activity who were started on reduced doses of AZA did not develop acute leukopenia.
Regueiro
Miguel
M
University of Pittsburg School of Medicine, Inflammatory Bowl Disease Center, Presbyterian Hospital, PA 15261, USA. regueirom@msx.dept-med.pitt.edu
Mardini
Houssam
H
D000293:Adolescent; D000328:Adult; D001379:Azathioprine / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism; D003424:Crohn Disease / Q000188:drug therapy*; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008780:Methyltransferases / Q000235:genetics*; D008875:Middle Aged; D010641:Phenotype; D012189:Retrospective Studies
D007166:Immunosuppressive Agents; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine