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Thiopurines: Pretreatment testing and approach to therapeutic drug monitoring for adults with inflammatory bowel disease

Thiopurines: Pretreatment testing and approach to therapeutic drug monitoring for adults with inflammatory bowel disease
Authors:
David T Rubin, MD
Nathaniel Aviv Cohen, MBBCh
Section Editor:
Sunanda V Kane, MD, MSPH
Deputy Editor:
Kristen M Robson, MD, MBA, FACG
Literature review current through: Jan 2024.
This topic last updated: Oct 14, 2022.

INTRODUCTION — The thiopurines (ie, azathioprine [AZA] and mercaptopurine, also known as 6-mercaptopurine [6-MP]) exert a glucocorticoid-sparing effect for patients with inflammatory bowel disease (IBD) who cannot maintain remission when glucocorticoids are tapered or withdrawn. Nonetheless, drug-related adverse events such as bone marrow suppression and hepatotoxicity may limit thiopurine use. Strategies for reducing the risk of adverse events, improving tolerability, and improving disease control include pretreatment screening for thiopurine methyltransferase (TPMT) enzyme activity, routine laboratory monitoring, and therapeutic drug monitoring [1].

This topic will review pretreatment evaluation and approach to therapeutic drug monitoring for patients with IBD on thiopurine therapy. The discussion is generally consistent with the American Gastroenterological Association (AGA) guideline on therapeutic drug monitoring for patients with IBD [2].

The pharmacology and empiric dosing of thiopurines for patients with IBD are discussed in more detail separately. (See "Overview of azathioprine and mercaptopurine use in inflammatory bowel disease".)

Medical management of Crohn disease (CD) and ulcerative colitis is discussed separately.

●(See "Overview of the medical management of mild (low risk) Crohn disease in adults".)

●(See "Medical management of moderate to severe Crohn disease in adults".)

●(See "Medical management of low-risk adult patients with mild to moderate ulcerative colitis".)

●(See "Management of moderate to severe ulcerative colitis in adults".)

●(See "Management of the hospitalized adult patient with severe ulcerative colitis".)

DRUG METABOLISM

Thiopurine metabolites — Thiopurines that are typically used for treating IBD include azathioprine (AZA) and 6-mercaptopurine (6-MP). AZA is a prodrug that is metabolized to 6-MP, which is then further metabolized along an anabolic pathway to several metabolites including 6-thioguanine (6-TG) and 6-methylmercaptopurine (6-MMP). Thiopurine methyltransferase (TPMT) is one of the key enzymes in thiopurine metabolism (figure 1). Patients with low or absent TPMT enzyme activity can develop bone marrow toxicity with thiopurine therapy due to excess production of 6-TG metabolites, while elevated 6-MMP levels have been associated with hepatotoxicity [3]. (See "Overview of azathioprine and mercaptopurine use in inflammatory bowel disease", section on 'Pharmacology'.)

Genetic factors affecting drug metabolism — Genetic polymorphisms of the TPMT gene can result in functional inactivation or markedly decreased activity of the enzyme and an increased risk of treatment-related leukopenia [4-7]. Approximately 10 percent of the general population have reduced TPMT activity and 0.3 percent (1 in 300) of the population have very low or absent activity [8]. TPMT enzyme activity is a major factor determining thiopurine metabolism, and thus, it affects 6-TG and 6-MMP levels (figure 1).

Pretreatment determination of TPMT genotype to guide dosing has been shown to be effective at reducing the risk of thiopurine-related bone marrow suppression (most frequently leukopenia) [9]. (See "Approach to the adult with unexplained neutropenia".)

Variants in another metabolizing enzyme, NUDT15 (nucleoside diphosphate-linked moiety X motif 15, NUDIX 15), have been identified that strongly influence thiopurine tolerance in patients with IBD [10]. The NUDT15 poor metabolizer phenotype has been observed primarily in Asian populations (up to 29 percent of individuals), but it is also common in Hispanic populations (21 percent) and, to a lesser degree, in European populations (3 percent) [11-14]. Homozygous carriers of NUDT15 variants are extremely intolerant of thiopurine compounds because of risk of bone marrow suppression. (See "Overview of pharmacogenomics", section on 'Thiopurines and polymorphisms in TPMT and NUDT15'.)

Data on other genetic polymorphisms are emerging and may provide further insight for individualizing dosing regimens for patients on thiopurine therapy [15,16].

PRETREATMENT EVALUATION

Assessing TPMT enzyme activity — For patients with IBD who are evaluated for treatment with a thiopurine (eg, azathioprine [AZA], 6-mercaptopurine [6-MP]), we assess thiopurine methyltransferase (TPMT) enzyme activity with phenotype testing before starting therapy, and this approach is consistent with society guidelines [2,17]. TPMT activity can be assessed by directly measuring enzyme activity in erythrocytes (phenotyping) or by genotype testing. The choice of testing varies by clinician preference, local laboratory availability, and cost. Of note, TPMT phenotype testing is generally preferred because the TPMT gene is highly polymorphic, and genotypic testing may misclassify some patients [18]. In addition, TPMT phenotype testing is typically a less costly option.

TPMT phenotype or genotype testing is suggested but not required by the US Food and Drug Administration (FDA) prior to thiopurine use.

It is important to recognize that patients with normal TPMT activity can develop bone marrow and/or liver toxicity in a dose-related fashion; thus, routine laboratory monitoring is required for all patients [19]. (See 'Routine laboratory monitoring' below.)

In the United States, testing for TPMT enzyme activity (phenotyping) is more commonly available and used in clinical practice, while TPMT genotypes have been correlated with TPMT activity (see 'Therapeutic drug monitoring' below) [3,20]:

●Normal TPMT activity – The majority of the general population have the most common TPMT alleles (wild type), and this genotype has been associated with normal enzyme activity (12 to 15 units/mL). For patients with normal enzyme activity, we typically begin a low dose thiopurine (eg, 6-MP 25 mg daily) and gradually increase the dose to a target, weight-based dose.

An alternative approach that is preferred by some clinicians is to initiate AZA or 6-MP at the target, weight-based dose (maximum dose: AZA 2.5 mg/kg daily or 6-MP 1.5 mg/kg daily) rather than starting low dose AZA or 6-MP and gradually increasing the dose until the target dose is achieved.

Some patients have above normal TPMT activity (>15 units/mL), which has been associated with lower rates of clinical remission [21]. For such patients, the approach to monitoring and dose adjustments is unchanged (ie based on 6-thioguanine (6-TG) levels and routine laboratory studies).

●Intermediate TPMT activity – Approximately 10 percent of the general population is heterozygous for a variant TPMT allele and has intermediate enzyme activity (5 to 12 units/mL). For patients with intermediate enzyme activity, we begin a low dose thiopurine (eg, 6-MP 25 mg daily) and gradually increase the dose to a target weight-based dose. Dose escalation is based on 6-TG levels (obtained every four weeks) and other laboratory parameters (eg, white blood cell count, obtained two weeks after any dose increase).

●Low or absent TPMT activity – Approximately 0.3 percent (1 in 300) of the general population is homozygous for TPMT variants and thus have low or absent activity (<5 unit/mL). The lack of enzyme activity causes thiopurines to be preferentially metabolized to produce high levels of 6-TG, which then leads to bone marrow toxicity and leukopenia. We do not use thiopurines for patients who have low or absent enzyme activity (or are homozygous for TPMT variants) to avoid risk of potentially life-threatening toxicity [22].

Dosing for AZA and 6-MP, including dose adjustments based on routine laboratory monitoring (eg, complete blood count [CBC]), is discussed in more detail separately. (See "Overview of azathioprine and mercaptopurine use in inflammatory bowel disease", section on 'Dosing and monitoring'.)

Evaluating for drug-drug interactions — Coexisting medications can affect thiopurine metabolism. As an example, mesalamine can reversibly inhibit TPMT activity and thus lead to corresponding increases in 6-TG levels with resultant leukopenia [23-25]. However, patients on mesalamine and a thiopurine do not require more frequent laboratory monitoring. (See 'Routine laboratory monitoring' below.)

Allopurinol inhibits the enzyme xanthine oxidase and should be avoided, since concomitant use of allopurinol and a thiopurine can potentially lead to life-threatening bone marrow suppression. However, for patients with thiopurine resistance, investigational use of allopurinol has been reported. (See 'Patients with thiopurine resistance' below.)

For more detailed information on potential drug-drug interactions, refer to the drug interactions program within UpToDate. Such drug interaction programs are meant to be a general guide, and consultation with a clinical pharmacist may provide more specific insight.

Is there a role for assessing other polymorphisms? — The recognition of NUDT15 as an additional genetic polymorphism affecting thiopurine metabolism has added to our understanding of clinical response to thiopurine therapy and risk of drug toxicity. Although consensus guidelines regarding testing for NUDT15 polymorphisms are lacking, we test patients who are at higher risk for this polymorphism (eg, Asian individuals, Hispanic individuals). Similar to TPMT testing, NUDT15 genotypes correlate with metabolic activity that is classified as normal, intermediate, or poor/limited. We adjust thiopurine dosing with an approach that is similar to dose adjustments related to TPMT activity [15]. (See 'Assessing TPMT enzyme activity' above.)  

We do not routinely test for NUDT15 polymorphisms in other populations because data to support such testing are limited. (See 'Drug metabolism' above.)

For patients with normal TPMT activity who unexpectedly develop leukopenia when a thiopurine is initiated, a polymorphism such as NUDT15 may be suspected, and some clinicians perform NUDT15 genotyping in this setting. Screening for genetic factors that influence drug metabolism is discussed in more detail separately. (See "Overview of pharmacogenomics", section on 'Thiopurines and polymorphisms in TPMT and NUDT15'.)

ROUTINE LABORATORY MONITORING — For patients who begin thiopurine therapy, laboratory testing (ie, complete blood count [CBC], serum aminotransferases, total bilirubin, and amylase) is typically performed weekly for the first four weeks, then every two weeks for weeks five through 12, and at least every three months thereafter. In addition, laboratory testing is performed in two weeks following dose escalation. Laboratory monitoring and dose adjustment for patients with cytopenia (eg, leukopenia, thrombocytopenia) are discussed separately. (See "Overview of azathioprine and mercaptopurine use in inflammatory bowel disease", section on 'Dosing and monitoring'.)

Long-term, routine laboratory monitoring is an essential aspect of care because patients with normal TPMT activity can develop bone marrow suppression and/or liver toxicity at any time during treatment [26].

THERAPEUTIC DRUG MONITORING

General principles — Therapeutic drug monitoring uses sampling of plasma or serum drug levels to determine optimal drug dosing. This technique has been applied to several therapeutic areas including antibiotics and immunosuppressive drugs such as anti-tumor necrosis factor (TNF) agents. (See "Treatment of Crohn disease in adults: Dosing and monitoring of tumor necrosis factor-alpha inhibitors", section on 'Monitoring'.)

For patients with IBD, therapeutic drug monitoring is one of several methods that are used for assessing clinical response. Other important methods include monitoring symptoms, evaluating endoscopic appearance and histology, and routine laboratory monitoring. For example, some adverse reactions (such as pancreatitis) can occur unrelated to elevated 6-thioguanine (6-TG) or 6-methylmercaptopurine (6-MMP) levels [27]. Thus, measuring metabolite levels does not replace other monitoring techniques including routine, long-term laboratory monitoring. In addition, therapeutic drug monitoring with metabolite testing may not be available in some clinical laboratories. (See 'Routine laboratory monitoring' above.)

For patients with IBD, thiopurine metabolite monitoring (ie 6-TG and 6-MMP) may be used for:

●Patients with active disease despite thiopurine therapy

●Patients with adverse effects (eg, leukopenia) that are possibly due to thiopurine therapy

Therapeutic drug monitoring in the setting of suboptimal disease control is referred to as reactive testing or monitoring [2].

Drug adjustments based on metabolite levels — For patients with active IBD despite thiopurine therapy, studies have suggested that certain 6-TG levels correlate with therapeutic efficacy and bone marrow toxicity, while markedly elevated 6-MMP levels correlate with hepatotoxicity [27-36]:

●6-TG level <230 picomoles/8 X 108 erythrocytes – Low or absent 6-TG levels are suggestive of noncompliance, suboptimal thiopurine dosing, or preferential metabolism to 6-MMP instead of 6-TG [33,37]. For patients with low or absent 6-TG levels, we confirm that the patient is compliant and that 6-MMP levels and complete blood count (CBC) are normal. For such patients, we increase the thiopurine dose. Routine laboratory monitoring is performed with every dose increase and this is discussed separately. (See "Overview of azathioprine and mercaptopurine use in inflammatory bowel disease", section on 'Dosing and monitoring'.)

●6-TG level between 230 and 450 picomoles/8 X 108 erythrocytes – A commonly used target level for 6-TG is between 230 and 450 picomoles/8 X 108 erythrocytes because this range has been associated with therapeutic efficacy.

●6-TG level >450 picomoles/8 X 108 erythrocytes – 6-TG levels >450 picomoles/8 X 108 erythrocytes have been associated with increased risk for developing bone marrow suppression [38]. The management of patients with cytopenia in the setting of thiopurine use is discussed separately. (See "Overview of azathioprine and mercaptopurine use in inflammatory bowel disease", section on 'Dose adjustment for cytopenia'.)

●6-MMP level >5700 picomoles/8 X 108 erythrocytes – 6-MMP concentrations >5700 picomoles/8 X 108 erythrocytes have been associated with increased risk for developing hepatotoxicity [29]. However, 6-MMP levels are not a highly accurate predictor of hepatotoxicity in all patients [39]. Dose adjustment for patients with normal liver biochemical tests but with elevated 6-MMP levels includes administering the thiopurine in divided doses. Dividing the daily dose has been shown to decrease 6-MMP levels without affecting 6-TG levels, thus reducing the development of adverse effects without compromising clinical benefit [40]. The rationale behind this method is that it reduces thiopurine methyltransferase (TPMT) induction during treatment, allowing more drug to be converted to 6-TG [41].

Dose-optimization or toxicity-avoidance strategies based upon drug metabolite monitoring have been associated with improved clinical outcomes. In an observational study of 63 patients with active IBD, using 6-TG and 6-MMP concentrations to guide treatment (eg, dose adjustment, switching to a different medication) was associated with higher rates of clinical response compared with no drug monitoring (86 versus 17 percent; risk ratio [RR] 5.15, CI 1.82-14.56) [3,42].

Other factors affecting metabolite levels — In addition to genetic polymorphisms, other factors may affect 6-TG levels:

●Factors associated with subtherapeutic 6-TG levels – Obesity has been associated with lower 6-TG levels. As an example, in a study including 132 patients with IBD, body mass index ≥30 kg/m2 was associated with higher rates of subtherapeutic 6-TG levels (ie <230 picomoles/8 X 108 erythrocytes) compared with normal body mass index (65 versus 35 percent) [43].

●Factors associated with elevated 6-TG levels include:

•Lifestyle factors – Tobacco use and chronic alcohol use have been identified as risk factors for elevated 6-TG levels [43,44]. Chronic alcohol consumption, through the depletion of S-adenosylmethionine (which is essential for TPMT enzyme activity), may increase 6-TG levels and thus increase risk of bone marrow suppression [44].

•Coexisting medications – Higher levels of 6-TG have been reported in patients on other IBD medications such as mesalamine [45]. Loop diuretics may have the potential to increase 6-TG levels by inhibiting TPMT enzyme activity [46]. (See 'Evaluating for drug-drug interactions' above.)

Another limitation to measuring metabolite levels is that the available testing does not distinguish between the three phosphorylated forms of thiopurine metabolites. The most common phosphate form of thiopurine metabolites is 6-thioguanosine triphosphate (6-TGTP), which is responsible for most of the bioactivity. 6-TGTP levels >100 picomoles/8 X 108 erythrocytes have been associated with clinical response [47]. Methods for detecting different metabolite forms are less accurate than conventional testing; however, more accurate methods of determining these levels may be available in the future.

SPECIAL POPULATIONS

Patients with thiopurine resistance — Patients who do not respond to initial dosing of thiopurines and/or to dose escalation are described as having thiopurine resistance [37]. For such patients, dose escalation of either azathioprine (AZA) or 6-mercaptopurine (6-MP) does not typically result in therapeutic 6-thioguanine (6-TG) levels, but rather leads to increased 6-methylmercaptopurine (6-MMP) levels and hepatoxicity.

For patients with thiopurine resistance, an investigational approach has been to use allopurinol that results in shunting of 6-MMP metabolites with a subsequent shift in drug metabolism towards 6-TG [48-50]. However, additional studies are needed to assess the efficacy and safety of this strategy before it can be used routinely in clinical practice. Because of the increased risk of bone marrow toxicity and leukopenia, the use of allopurinol for managing thiopurine resistance remains investigational.

Patients treated with combination therapy — For patients who are initiating a thiopurine as part of combination therapy (eg, an anti-tumor necrosis factor [TNF] agent plus a thiopurine), we use the pretreatment testing and drug monitoring strategies as described above. (See 'Pretreatment evaluation' above and 'Therapeutic drug monitoring' above.)

Preliminary data suggest that testing for selected genetic variants may help identify patients who are at increased risk for developing anti-drug antibodies with anti-TNF therapy and who may benefit from the addition of a thiopurine [51]. The use of combination therapy for patients with IBD including pretreatment testing and drug monitoring with anti-TNF therapy is discussed in more detail separately. (See "Medical management of moderate to severe Crohn disease in adults", section on 'Combination therapy' and "Treatment of Crohn disease in adults: Dosing and monitoring of tumor necrosis factor-alpha inhibitors".)

Asian populations — Data have suggested that Asian individuals required a lower thiopurine dose and were at higher risk for leukopenia [52-54]. As an example, in a study including 252 Asian individuals with IBD, 6-TG levels of 180 to 355 picomoles/8 X 108 erythrocytes were associated with clinical remission, and this range is lower than the reference range used for the general population [52]. (See 'General principles' above.)

In addition, testing for TPMT activity prior to initiating thiopurine therapy may not be useful for Asian individuals because genetic polymorphisms in the TPMT enzyme are rare in such patients and testing for other polymorphisms such as NUDT15 is more appropriate [54]. (See 'Is there a role for assessing other polymorphisms?' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ulcerative colitis in adults" and "Society guideline links: Crohn disease in adults".)

SUMMARY AND RECOMMENDATIONS

●Background – The thiopurines (ie, azathioprine [AZA] and 6-mercaptopurine [6-MP]) exert a glucocorticoid-sparing effect for patients with inflammatory bowel disease (IBD) who cannot maintain remission when glucocorticoids are tapered or withdrawn. However, drug-related adverse events such as bone marrow suppression and hepatotoxicity may limit thiopurine use. Strategies for reducing the risk of adverse events and improving tolerability include pretreatment screening for thiopurine methyltransferase (TPMT) enzyme activity and routine laboratory and therapeutic drug monitoring during treatment. (See 'Introduction' above.)

●Drug metabolism – TPMT enzyme activity is a major factor determining thiopurine metabolism, and thus, it affects metabolite levels (eg, 6-thioguanine [6-TG], 6-methylmercaptopurine [6-MMP]) (figure 1). Genetic polymorphisms of the TPMT gene can result in markedly decreased or absent activity of the enzyme and an increased risk of treatment-related leukopenia. Approximately 10 percent of the general population have reduced TPMT activity and 0.3 percent (1 in 300) have very low or absent activity. (See 'Drug metabolism' above.)

●Pretreatment evaluation – For patients with IBD who are evaluated for treatment with a thiopurine, we assess TPMT enzyme activity with phenotype testing before starting therapy. In selected patients (eg, Asian individuals, Hispanic individuals), we assess for NUDT15 polymorphisms.

TPMT activity can be assessed by directly measuring enzyme activity in erythrocytes (phenotyping) (see 'Pretreatment evaluation' above and "Overview of azathioprine and mercaptopurine use in inflammatory bowel disease"):

•For patients with normal or intermediate enzyme activity, we begin a low dose thiopurine (eg, 6-MP 25 mg daily) and gradually increase the dose to a target, weight-based dose.

•For patients with very low or absent enzyme activity, we avoid thiopurines because of the risk of bone marrow toxicity.

●Routine laboratory monitoring – Long-term, routine laboratory monitoring is an essential aspect of care because patients with normal TPMT activity can develop bone marrow suppression and/or liver toxicity at any time during treatment. For patients who begin thiopurine therapy, laboratory testing (ie, complete blood count [CBC], serum aminotransferases, total bilirubin, and amylase) is typically performed weekly for the first four weeks, then every two weeks for weeks five through 12, and at least every three months thereafter. In addition, laboratory testing is performed in two weeks following any dose escalation. (See 'Routine laboratory monitoring' above.)

●Therapeutic drug monitoring – For patients with IBD, thiopurine metabolite monitoring (ie 6-TG and 6-MMP) may be used for (see 'General principles' above):

•Patients with active disease despite thiopurine therapy

•Patients with adverse effects (eg, leukopenia) that are possibly due to thiopurine therapy

For patients with active IBD despite thiopurine therapy, certain 6-TG levels correlate with therapeutic efficacy (230 and 450 picomoles/8 X 108 erythrocytes) or bone marrow toxicity (>450 picomoles/8 X 108 erythrocytes), while markedly elevated 6-MMP levels correlate with hepatotoxicity. In addition to monitoring routine laboratory values (eg, CBC) and symptoms, thiopurine metabolite levels can also be used to guide drug dose adjustments. (See 'Drug adjustments based on metabolite levels' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff thank Richard P MacDermott, MD for his contributions as author to prior versions of this topic review.

The UpToDate editorial staff also acknowledges Paul Rutgeerts, MD (deceased), who contributed as a section editor for UpToDate in Gastroenterology.

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  48. Sparrow MP, Hande SA, Friedman S, et al. Allopurinol safely and effectively optimizes tioguanine metabolites in inflammatory bowel disease patients not responding to azathioprine and mercaptopurine. Aliment Pharmacol Ther 2005; 22:441.
  49. Sparrow MP, Hande SA, Friedman S, et al. Effect of allopurinol on clinical outcomes in inflammatory bowel disease nonresponders to azathioprine or 6-mercaptopurine. Clin Gastroenterol Hepatol 2007; 5:209.
  50. Rahhal RM, Bishop WP. Initial clinical experience with allopurinol-thiopurine combination therapy in pediatric inflammatory bowel disease. Inflamm Bowel Dis 2008; 14:1678.
  51. Sazonovs A, Kennedy NA, Moutsianas L, et al. HLA-DQA1*05 Carriage Associated With Development of Anti-Drug Antibodies to Infliximab and Adalimumab in Patients With Crohn's Disease. Gastroenterology 2020; 158:189.
  52. Feng R, Guo J, Zhang SH, et al. Low 6-thioguanine nucleotide level: Effective in maintaining remission in Chinese patients with Crohn's disease. J Gastroenterol Hepatol 2019; 34:679.
  53. Jung ES, Choi KW, Kim SW, et al. ZNF133 is associated with infliximab responsiveness in patients with inflammatory bowel diseases. J Gastroenterol Hepatol 2019; 34:1727.
  54. Zhang JP, Guan YY, Wu JH, et al. Phenotyping and genotyping study of thiopurine S-methyltransferase in healthy Chinese children: a comparison of Han and Yao ethnic groups. Br J Clin Pharmacol 2004; 58:163.
Topic 4058 Version 36.0

References

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13 : Analysis of protein-coding genetic variation in 60,706 humans.

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34 : Therapeutic drug monitoring of azathioprine and 6-mercaptopurine metabolites in Crohn disease.

35 : 6-tioguanine monitoring in steroid-dependent patients with inflammatory bowel diseases receiving azathioprine.

36 : Association between 6-thioguanine nucleotides levels and clinical remission in inflammatory disease: a meta-analysis.

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38 : A 6-thioguanine nucleotide threshold level of 400 pmol/8 x 10(8) erythrocytes predicts azathioprine refractoriness in patients with inflammatory bowel disease and normal TPMT activity.

39 : Hepatotoxicity of 6-mercaptopurine (6-MP) and Azathioprine (AZA) in adult IBD patients.

40 : Split-dose administration of thiopurine drugs: a novel and effective strategy for managing preferential 6-MMP metabolism.

41 : Human thiopurine S-methyltransferase activity in uremia and after renal transplantation.

42 : Clinical usefulness of therapeutic drug monitoring of thiopurines in patients with inadequately controlled inflammatory bowel disease.

43 : Body Mass Index and Smoking Affect Thioguanine Nucleotide Levels in Inflammatory Bowel Disease.

44 : Genetic variation in the MTHFR gene influences thiopurine methyltransferase activity.

45 : Tolerability and safety of mercaptopurine in azathioprine-intolerant patients with inflammatory bowel disease.

46 : Inhibition of human thiopurine methyltransferase by furosemide, bendroflumethiazide and trichlormethiazide.

47 : 6-thioguanosine diphosphate and triphosphate levels in red blood cells and response to azathioprine therapy in Crohn's disease.

48 : Allopurinol safely and effectively optimizes tioguanine metabolites in inflammatory bowel disease patients not responding to azathioprine and mercaptopurine.

49 : Effect of allopurinol on clinical outcomes in inflammatory bowel disease nonresponders to azathioprine or 6-mercaptopurine.

50 : Initial clinical experience with allopurinol-thiopurine combination therapy in pediatric inflammatory bowel disease.

51 : HLA-DQA1*05 Carriage Associated With Development of Anti-Drug Antibodies to Infliximab and Adalimumab in Patients With Crohn's Disease.

52 : Low 6-thioguanine nucleotide level: Effective in maintaining remission in Chinese patients with Crohn's disease.

53 : ZNF133 is associated with infliximab responsiveness in patients with inflammatory bowel diseases.

54 : Phenotyping and genotyping study of thiopurine S-methyltransferase in healthy Chinese children: a comparison of Han and Yao ethnic groups.

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