title: Successful azathioprine treatment with metabolite monitoring in a pediatric inflammatory bowel disease patient homozygous for TPMT*3C.
abstract: Thiopurine S-methyltransferase (TPMT) methylates purine analogues, showing TPMT activity in inverse relation to concentrations of active metabolites such as 6-thioguanine nucleotide (6-TGN). With conventional dosing of thiopurines, patients with homozygous variant TPMT alleles consistently suffer from severe myelosuppression. Here, we report a patient with TPMT*3C/*3C who managed successfully with monitoring of thiopurine metabolites. The patient was an 18-year-old male diagnosed with Crohn's disease. The standard dose of azathioprine (AZA) (1.8 mg/kg/day) with mesalazine (55.6 mg/kg/day) was prescribed. Two weeks after starting AZA treatment, the patient developed leukopenia. The DNA sequence analysis of TPMT identified a homozygous missense variation (NM_000367.2: c.719A>G; p.Tyr240Cys), TPMT*3C/*3C. He was treated with adjusted doses of azathioprine (0.1-0.2 mg/kg/day) and his metabolites were closely monitored. Leukopenia did not reoccur during the follow-up period of 24 months. To our knowledge, this is the first case of a patient homozygous for TPMT*3C successfully treated with azathioprine in Korea. While a TPMT genotyping test may be helpful to determine a safe starting dose, it may not completely prevent myelosuppression. Monitoring metabolites as well as routine laboratory tests can contribute to assessing drug metabolism and optimizing drug dosing with minimized drug-induced toxicity.
authors.affiliation: Department of Laboratory Medicine and Genetics, Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135-710, Korea. suddenbz@skku.edu.
authors.forename: Mi-Na
authors.initials: MN
authors.lastname: Lee
authors.forename: Hye In
authors.initials: HI
authors.lastname: Woo
authors.forename: Yoo Min
authors.initials: YM
authors.lastname: Lee
authors.forename: Ben
authors.initials: B
authors.lastname: Kang
authors.forename: Jong-Won
authors.initials: JW
authors.lastname: Kim
authors.forename: Yon Ho
authors.initials: YH
authors.lastname: Choe
authors.forename: Soo-Youn
authors.initials: SY
authors.lastname: Lee
mesh_terms: D000293:Adolescent; D001379:Azathioprine / Q000009:adverse effects / Q000627:therapeutic use*; D006720:Homozygote; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008780:Methyltransferases / Q000235:genetics*
chemical_list: D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine
keywords: Thiopurine methyltransferase; azathioprine; inflammatory bowel disease; metabolite levels