Thiopurines in inflammatory bowel disease: pharmacogenetics, therapeutic drug monitoring and clinical recommendations

Hadithy, Asmar Faris Yassin Drs Al; Boer, Nanne K. H. de; Derijks, Luc J. J.; Escher, J.C.; Mulder, Chris J.; Brouwers, Jacobus

doi:10.1016/j.dld.2004.09.029

Cited by 98 publications

(88 citation statements)

References 172 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…1 Both patients who developed this histological liver abnormality had one mutant TPMT allele, probably leading to an impaired ability to methylate AZA-generated metabolites and subsequently to an overproduction of the pharmacologically active end metabolites 6-thioguaninenucleotides (6-TGN). 2 We believe that NRH may not be caused by the TPMT activity itself but is attributable to the generated 6-TGN concentrations. Recently, the use of the thiopurine 6-thioguanine (6-TG) in inflammatory bowel disease (IBD) patients has been discarded due to its presumed role in inducing NRH.…”

Section: To the Editorsmentioning

confidence: 99%

Nodular regenerative hyperplasia and thiopurines: The case for level-dependent toxicity

2005

View full text Add to dashboard Cite

To the Editors:In a recent study by Breen et al., a possible causal role of the key enzyme thiopurine methyltransferase (TPMT) in inducing nodular regenerative hyperplasia (NRH) during azathioprine (AZA) treatment in liver transplant patients was considered. 1 Both patients who developed this histological liver abnormality had one mutant TPMT allele, probably leading to an impaired ability to methylate AZA-generated metabolites and subsequently to an overproduction of the pharmacologically active end metabolites 6-thioguaninenucleotides (6-TGN). 2 We believe that NRH may not be caused by the TPMT activity itself but is attributable to the generated 6-TGN concentrations. Recently, the use of the thiopurine 6-thioguanine (6-TG) in inflammatory bowel disease (IBD) patients has been discarded due to its presumed role in inducing NRH. 3 A major pharmacokinetic difference between AZA and 6-TG is that during 6-TG administration (40 to 80 mg), much higher 6-TGN levels (Ͼ1,000 pmol/10 8 per red blood cell [RBC]) are achieved than during AZA treatment (normally between 100 and 500 pmol/10 8 RBC). 2 These relatively high 6-TGN levels may explain the alleged elevated risk of developing NRH during 6-TG therapy. Our liver histological data concerning the use of low-dose 6-TG for treating IBD patients intolerant or refractory to AZA therapy support this hypothesis (Table 1). At our hospital, a liver biopsy is routinely performed in patients who use 6-TG for at least one year. In addition, 6-TGN levels are regularly monitored. The fact that we have not encountered one case of NRH may well be explained by the relatively low 6-TGN levels (mean 442 pmol/10 8 RBC) achieved as a consequence of the prescribed 6-TG dosages (approximately 0.3 mg/kg). The induction of NRH during thiopurine treatment in general may be 6-TGN dependent. This hypothesis explains the relatively low but well-documented incidence of NRH during AZA treatment as high 6-TGN levels are merely found in those patients with impaired TPMT activity (approximately 10% of the population) and would also provide an answer for the high incidence of NRH during highdose 6-TG treatment. We therefore consider low-dose 6-TG (0.3 mg/kg) as a therapeutic alternative, but until more long-term toxicity data are available, 6-TG use should preferably be restricted to trials with a regular performance of liver biopsies.

show abstract

Section: To the Editorsmentioning

confidence: 99%

Nodular regenerative hyperplasia and thiopurines: The case for level-dependent toxicity

2005

View full text Add to dashboard Cite

show abstract

“…5,6 The metabolites suppress the overactive immune systems in patients with inflammatory bowel disease due to their structural similarity to the endogenous purine bases. After oral administration approximately 90% of absorbed azathioprine undergoes a rapid non-enzymatic hepatic conversion yielding 6-MP and methyl-4-nitro-imidazol.…”

Section: Metabolism and Pharmacologymentioning

confidence: 99%

“…3,4 Different approaches to optimise therapy have been proposed and pharmacogenetics is one such approach. 5 Thiopurine S-methyltransferase (TPMT) is involved in the metabolism of thiopurines and is known to exhibit genetic polymorphism. Therefore, variations within TPMT activity may modulate the clinical response to thiopurines in inflammatory bowel disease and other diseases.…”

Section: Introductionmentioning

confidence: 99%

Thiopurines for Inflammatory Bowel Disease: Role of Pharmacogenetics

Hadithy

Naunton

Brouwers³

2005

Pharmacy Practice and Res

View full text Add to dashboard Cite

There is a growing interest in the use of thiopurines for inflammatory bowel disease. Pharmacogenetic insights suggest that the genetic profile of thiopurine S-methyltransferase and inosine triphosphate pyrophosphatase may affect the clinical response to thiopurines. This is a review on the pharmacogenetics of these enzymes and highlights difficulties that impede priorto-treat pharmacogenetic testing for the thiopurines in practice.

show abstract

“…Patients with heterozygous genotype have intermediate enzyme activity and intermediate drug level in organism. In patients with high TPMT enzyme activity, the risk of hepatotoxicity is high because of huge production of methylated mercaptopurine metabolites damaging the liver (1,12). Ethnic differences between distribution of TPMT mutant alleles have been described (11,14,22).…”

mentioning

confidence: 99%

“…They compete with endogenous guanozine triphosphate (GTP) that is an essential part of signaling pathways and the source of energy for cells. In addition they infl uence the growth and proliferation of T and B lymphocytes and inhibit the activated immune system in IBD patients (1,12). After oral ingestion and absorption, 90 % of azathioprine is converted to 6-mercaptopurine by nonenzymatic reaction with contribution of glutathione or cystein (19).…”

mentioning

confidence: 99%

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

Desatova

Hlavatý²,

Balakova³

et al. 2013

BLL

View full text Add to dashboard Cite

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.

show abstract

Thiopurines in inflammatory bowel disease: pharmacogenetics, therapeutic drug monitoring and clinical recommendations

Cited by 98 publications

References 172 publications

Nodular regenerative hyperplasia and thiopurines: The case for level-dependent toxicity

Nodular regenerative hyperplasia and thiopurines: The case for level-dependent toxicity

Thiopurines for Inflammatory Bowel Disease: Role of Pharmacogenetics

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

Contact Info

Product

Resources

About