Adverse reactions to azathioprine cannot be predicted by thiopurine S‐methyltransferase genotype in Japanese patients with inflammatory bowel disease

Takatsu, Noritaka; Matsui, Toshiyuki; Murakami, Yuji; Ishiguro, Hiroshi; Hisabe, Takashi; Nishizaki, Takashi; Maki, Shinichirou; Beppu, Takahiro; Takaki, Yasuhiro; Hirai, Fumihito; Yao, Kenshi

doi:10.1111/j.1440-1746.2009.05917.x

Cited by 134 publications

(130 citation statements)

References 28 publications

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“…Many patients with high level tolerated this metabolite level. It is previously reported that Asians have higher likelihood of thiopurine toxicity 21, 34. We had lowest toxicity as compared with that reported in the literature and did not observe any hepatotoxicity.…”

Section: Discussionsupporting

confidence: 52%

“…There is a poor correlation between weight‐based dosing of thiopurines and 6‐TGN and 6‐MMP levels 26. Previous studies have suggested that Asian patients do not tolerate full doses of thiopurines and have more toxicity 10, 18, 19, 20, 21. However, as mentioned above, these studies were based on estimation of TPMT genotype and activity rather than drug metabolites.…”

Section: Discussionmentioning

confidence: 99%

“…It is reported that the thiopurine metabolism differs in Asian patients who do not tolerate full dose of thiopurine 10, 18, 19, 20, 21. However, these studies were based on TPMT genotype and activity rather than metabolite estimation.…”

Section: Introductionmentioning

confidence: 99%

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Thiopurine metabolite level and toxicity in Indians with inflammatory bowel disease

et al. 2017

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Background and AimA lower dose requirement and higher toxicity of thiopurine is reported in Asian patients with inflammatory bowel disease (IBD) as compared with Caucasian patients. These reports are based on thiopurine methyltransferase measurement studies rather than metabolite estimation.We studied the utility of thiopurine metabolite estimation in Indian patients with IBD and compared dose and toxicity with Asian and Caucasian patients.MethodsIn this prospective study, 6‐thioguanine nucleotide (6‐TGN) and 6‐methylmercaptopurine levels were determined by HPLC in 76 IBD patients treated with thiopurines. The levels were correlated with dose, disease activity, and toxicity. The dose‐related metabolite levels and toxicity were compared with Caucasian and Asian patients reported in literature.ResultsOf the 76 patients (32 women, mean age: 35.9 [SD: 14.54] years, 36 Crohn's disease and 40 ulcerative colitis), 1 non‐compliant patient had undetectable level of metabolites. Of the 75 patients, 21(28%) had therapeutic level of 6‐TGN, 37(49%) had subtherapeutic level and 17(23%) had supratherapeutic level. The 6‐methylmercaptopurine levels ranged up to 4971 pmol/8 × 108 red blood cells. Six (8%) patients showed toxicity. Thiopurine dose was optimized in 20 (26.31%) patients. Dose‐based metabolite levels were comparable to Asian and Caucasian patients. The toxicity (8%) observed in our patients was less than that reported (12–39%).ConclusionHalf of the patients in this study had low and a quarter had high 6‐TGN levels. One‐fourth of the patients needed dose modification. The dose‐based metabolite levels were comparable and the toxicity was less than that reported in Asian and Caucasian patients.

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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

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Thiopurine metabolite level and toxicity in Indians with inflammatory bowel disease

et al. 2017

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“…However, in 15-30% of patients, these drugs have to be discontinued due to adverse effects including bone marrow suppression, hepatotoxicity, pancreatitis, fever, rash and gastrointestinal intolerance (4)(5)(6)(7)(8)(9). Furthermore, an AZA dosage of 2-3 mg/kg is recommended for the treatment of IBD patients in Western countries (10), but lower doses of AZA (0.6-1.2 mg/kg/day) are used in Japanese patients due to their relatively heightened sensitivity (11).…”

Section: Introductionmentioning

confidence: 99%

Accuracy of genotyping using the TaqMan PCR assay for single nucleotide polymorphisms responsible for thiopurine sensitivity in Japanese patients with inflammatory bowel disease

Osaki¹,

Imaeda²,

Ban³

et al. 2011

Experimental and Therapeutic Medicine

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Abstract. Thiopurine drugs are the most common drugs used to maintain clinical remission in inflammatory bowel disease (IBD). Three single-nucleotide polymorphisms (SNPs), TPMT A719G (rs1142345), inosine triphosphate pyrophosphatase (ITPase) C94A (rs1127354) and multidrug resistance protein 4 MRP4 G2269A (rs3765534), have been reported to account for heightened sensitivity to thiopurine drugs in the Japanese population. We investigated the usefulness of the TaqMan ® PCR assay (Applied Biosystems) for the rapid detection of these SNPs to improve the safety of thiopurine therapy. We enrolled 44 healthy volunteers and 235 IBD patients. Genotyping of the SNPs was performed using Custom TaqMan SNP genotyping assays, direct sequencing and PCR-RFLP. Genotyping for MRP4 G2269A by the TaqMan PCR assay was successfully achieved in all samples. Comparison with our previous data using direct sequencing indicated one discordant result, and re-sequencing showed that the TaqMan PCR assay was correct. The overall accuracy of the TaqMan assay for MRP4 G2269A was 100%. The TaqMan PCR genotyping for TPMT A719G and ITPase C94A was successfully performed in all samples. The results of TPMT A719G by the TaqMan assay were identical with those of PCR-RFLP. In ITPase C94A, a comparison of the TaqMan assay and PCR-RFLP yielded 12 discordant results, and direct sequencing showed that the TaqMan PCR assay was correct. The allelic frequency determined by the TaqMan assay was 0.145 for MRP4 G2269A, 0.009 for TPMT A719G and 0.121 for ITPase C94A, respectively. In conclusion, the TaqMan ® PCR assay is useful for genotyping of SNPs responsible for thiopurine sensitivity in Japanese IBD patients.

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“…It catalyses the thiopurines S-methylation (4,17,22). TPMT enzyme activity is inherited as an autosomal codominant sign and is under the control of genetic polymorphisms that have been extensively studied in the past (21).…”

mentioning

confidence: 99%

Prevalence of mutations in thiopurine S-methyltransferase gene among Slovak IBD patients

Desatova

Hlavatý²,

Balakova³

et al. 2013

BLL

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Abstract:Background: Thiopurine S-methyltransferase (TPMT) plays an important role in the metabolism of thiopurines. It has been suggested that TPMT genetic polymorphisms lead to dose-related hematopoietic toxicity. Since there are major ethnic differences in the prevalence of particular TPMT variants, it is important for each country to study their own prevalence in order to estimate the role of TPMT variants-related thiopurines toxicity in population suffering from particular infl ammatory bowel disease (IBD). Aims: The aim of this study was to determine the frequency of the four most common allelic variants of TPMT gene in the population of Slovak IBD patients. Methods: TPMT genetic polymorphisms (TPMT*2, TPMT*3A, TPMT*3B, TPMT*3C) were amplifi ed using PCR and consequently genotyped with genetic analyzer. The allele frequencies of particular allelic variants were calculated and compared with other Caucasian populations reported so far. Results: Three hundred and thirty IBD patients were included; 196/132/2 cases of Crohn´s disease/ulcerative colitis/unclassifi ed colitis; 180 (55 %) males. Ninety-three percent of patients were homozygous for wild-type TPMT variant. Heterozygous genotype of any of the studied polymorphisms was present in 6 % of patients while only one patient was homozygous for TPMT*3A allele (0.3 %). The most prevalent mutant allele was that of TPMT*3A (3.2 %). The distribution of most common allelic variants of TPMT gene among Slovak IBD patients was in accordance with previously reported prevalence in Caucasian populations. Conclusion: This study shows the prevalence of TPMT genetic polymorphisms in population of Slovak IBD patients. As in other Caucasian populations, the most common mutant allelic variant is that of TPMT*3A while the prevalence of homozygosity is relatively low (Tab. 3, Ref. 22). Full Text in PDF www.elis.sk.

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Adverse reactions to azathioprine cannot be predicted by thiopurine S‐methyltransferase genotype in Japanese patients with inflammatory bowel disease

Cited by 134 publications

References 28 publications

Thiopurine metabolite level and toxicity in Indians with inflammatory bowel disease

Thiopurine metabolite level and toxicity in Indians with inflammatory bowel disease

Accuracy of genotyping using the TaqMan PCR assay for single nucleotide polymorphisms responsible for thiopurine sensitivity in Japanese patients with inflammatory bowel disease

Prevalence of mutations in thiopurine S-methyltransferase gene among Slovak IBD patients

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