title: A Prospective Study Evaluating Metabolic Capacity of Thiopurine and Associated Adverse Reactions in Japanese Patients with Inflammatory Bowel Disease (IBD).
abstract: Azathioprine (AZA) is frequently used in patients with inflammatory bowel disease (IBD). However, toxic adverse reactions frequently develop and limit the clinical benefits. Currently, the precise mechanisms underlying thiopurine-related toxicity are not well understood. To investigate the relationship between the extent of thiopurine metabolism and adverse reactions in Japanese IBD patients, we prospectively observed 48 IBD patients who received AZA. We analyzed the thiopurine S-methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) gene mutations and measured the concentrations of 6-thioguanine nucleotide (6-TGN) continuously for 52 weeks. All patients possessed wild-type TPMT gene sequences. The ITPA 94C>A mutation was detected in 19 patients (39.6%). Adverse reactions developed in 14 of the 48 patients (29.2%), including leukopenia in 10 patients (20.8%). In the leukopenia group, the percentages of patients with 94C>A were higher than those in the without-leukopenia group (70.0% vs. 31.6%, P < 0.05). The average concentrations of 6-TGN in the patients with 94C>A were generally higher than those in the patients without 94C>A, however, there were no significant differences. Only 3 out of 10 patients with leukopenia exhibited high 6-TGN levels (30.0%). No negative correlations between white blood cell (WBC) counts and 6-TGN concentrations were observed. The cumulative incidence of leukopenia were higher for patients with 94C>A. Seven out of 19 patients (36.8%) with the ITPA 94C>A mutation developed leukopenia; however, this mutation may not unequivocally increase the risk of developing leukopenia. In addition, there are factors other than increased 6-TGN levels that are involved in the onset of leukopenia.
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, The Jikei University School of Medicine (Kashiwa Hospital), Chiba, Japan.
authors.forename: Shunichi
authors.initials: S
authors.lastname: Odahara
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, The Jikei University School of Medicine (Kashiwa Hospital), Chiba, Japan.
authors.forename: Kan
authors.initials: K
authors.lastname: Uchiyama
authors.affiliation: Department of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kubota
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, The Jikei University School of Medicine (Kashiwa Hospital), Chiba, Japan.
authors.forename: Zensho
authors.initials: Z
authors.lastname: Ito
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, The Jikei University School of Medicine (Kashiwa Hospital), Chiba, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Takami
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, The Jikei University School of Medicine (Kashiwa Hospital), Chiba, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Kobayashi
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, The Jikei University School of Medicine (Kashiwa Hospital), Chiba, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Saito
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, The Jikei University School of Medicine (Kashiwa Hospital), Chiba, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Koido
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, The Jikei University School of Medicine (Kashiwa Hospital), Chiba, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Ohkusa
mesh_terms: D000328:Adult; D000483:Alleles; D001379:Azathioprine / Q000009:adverse effects* / Q000378:metabolism*; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D005838:Genotype; D006150:Guanine Nucleotides / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000378:metabolism*; D015994:Incidence; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D007564:Japan; D007970:Leukopenia / Q000453:epidemiology / Q000209:etiology; D008297:Male; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D010597:Pharmacogenetics; D011446:Prospective Studies; D011755:Pyrophosphatases / Q000235:genetics / Q000378:metabolism; D013873:Thionucleotides / Q000378:metabolism; D055815:Young Adult; D000097630:Inosine Triphosphatase
chemical_list: D001379:Azathioprine; D006150:Guanine Nucleotides; D007166:Immunosuppressive Agents; D008780:Methyltransferases; D011755:Pyrophosphatases; D013873:Thionucleotides; C003964:6-thioguanylic acid; C022745:thiopurine methyltransferase; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase