Yonsei Med J.  2013 Nov;54(6):1545-1549. 10.3349/ymj.2013.54.6.1545.

Successful Azathioprine Treatment with Metabolite Monitoring in a Pediatric Inflammatory Bowel Disease Patient Homozygous for TPMT*3C

• Lee MN
• Woo HI
• Lee YM
• Kang B
• Kim JW
• Choe YH
• Lee SY

• KMID: 1798157
• DOI: http://doi.org/10.3349/ymj.2013.54.6.1545

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.

Keyword

Thiopurine methyltransferase; azathioprine; inflammatory bowel disease; metabolite levels

MeSH Terms

Adolescent
Azathioprine/adverse effects/*therapeutic use
Homozygote
Humans
Inflammatory Bowel Diseases/*drug therapy/*enzymology/*genetics/metabolism
Male
Methyltransferases/*genetics
Azathioprine
Methyltransferases

Figure

• 

  Fig. 1 Absolute neutrophil count (ANC) and erythrocyte 6-thioguanine nucleotides (6-TGN) concentrations according to dosages of azathioprine. Leukopenia was developed 2 weeks after starting azathioprine (AZA). AZA was reduced and discontinued. After leukopenia was recovered, AZA treatment was restarted. The patient continued to receive AZA treatment with optimized daily dose adjustments (0.1-0.2 mg/kg) and ANC was maintained within normal limits by monitoring thiopurine metabolites such as 6-TGN. RBC, red blood cells; TPMT, thiopurine S-methyltransferase.

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