1.Successful Azathioprine Treatment with Metabolite Monitoring in a Pediatric Inflammatory Bowel Disease Patient Homozygous for TPMT*3C.
Mi Na LEE ; Hye In WOO ; Yoo Min LEE ; Ben KANG ; Jong Won KIM ; Yon Ho CHOE ; Soo Youn LEE
Yonsei Medical Journal 2013;54(6):1545-1549
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.
Adolescent
;
Azathioprine/adverse effects/*therapeutic use
;
Homozygote
;
Humans
;
Inflammatory Bowel Diseases/*drug therapy/*enzymology/*genetics/metabolism
;
Male
;
Methyltransferases/*genetics
2.Thiopurine methyltransferase gene polymorphisms and activity in Chinese patients with inflammatory bowel disease treated with azathioprine.
Chinese Medical Journal 2012;125(20):3665-3670
BACKGROUNDThe thiopurine drugs are well established in the treatment of inflammatory bowel disease (IBD). However, uncertainty regarding the risk for neutropenia and hepatotoxicity deters its using. Thiopurine methyltransferase (TPMT) is the key enzyme in the metabolism of thiopurine. The aim of this study was to investigate the association of TPMT polymorphisms and activity with azathioprine (AZA)-related adverse events and clinical efficacy in Chinese Han patients with IBD.
METHODSFifty-two Han IBD patients treated with AZA were assessed for TPMT 2, 3A, 3B, and 3C, and for adverse events. Then, using reverse-phase high-performance liquid chromatography, TPMT activity was measured in 13 patients to analyze its correlation with AZA-related toxicity and clinical efficacy.
RESULTSOf the 52 patients, five experienced myelotoxicity and one experienced hepatotoxicity during treatment. No TPMT 2, 3A, 3B or 3C polymorphisms were detected in any of the 52 patients. In the 13 patients with TPMT activity measurement, TPMT activity ranged from 7.2 to 28.8 U/ml packed red blood cells (pRBCs). Among the 5 patients who suffered from myelotoxicity, 3 were affected in the early stage of AZA therapy. In these 3 patients, TPMT levels were significantly lower than those in patients without myelotoxicity, which reached statistical significance ((9.3 ± 2.1) U/ml pRBC vs. (18.0 ± 6.2) U/ml pRBC; P = 0.046). One patient who had higher TPMT activity (28.8 U/ml pRBC) suffered from hepatotoxicity during AZA therapy. Patients who achieved a clinical response had lower TPMT activity than those failed to respond ((13.7 ± 3.5) U/ml pRBC vs. (22.0 ± 5.5) U/ml pRBC; P = 0.009).
CONCLUSIONSTPMT variants do not completely account for the AZA-related myelotoxicity in Chinese Han IBD patients. However, measurement of TPMT activity may be helpful in reducing the risk of toxicity, and predicting the therapeutic efficacy.
Adolescent ; Adult ; Aged ; Antimetabolites ; therapeutic use ; Azathioprine ; adverse effects ; therapeutic use ; Female ; Humans ; Inflammatory Bowel Diseases ; drug therapy ; enzymology ; Male ; Methyltransferases ; genetics ; metabolism ; Middle Aged ; Polymorphism, Genetic