Simultaneous determination of 6-thioguanine and methyl 6-mercaptopurine nucleotides of azathioprine in red blood cells by HPLC

Dervieux, Thierry; Boulieu, Roselyne

doi:10.1093/clinchem/44.3.551

Cited by 188 publications

(90 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Second, despite the results of a large meta‐analysis which pointed out that the optimal dose to enhance the chance of achieving clinical response to AZA was the weighted full dose of 2.5 mg/kg, a poor correlation between the weight‐adjusted oral dose and serum 6TGN levels has been documented 5, 42, 43 . Finally, the optimal method to measure 6TGN RBC levels still remains an unresolved question 13, 44–46 ; moreover, some authors have suggested that there should be some other metabolites that could be more useful in predicting poor response to thiopurines 47 …”

Section: Discussionmentioning

confidence: 99%

Thiopurine methyl-transferase activity and azathioprine metabolite concentrations do not predict clinical outcome in thiopurine-treated inflammatory bowel disease patients

González-Lama

Bermejo²,

López-Sanromán

et al. 2011

Alimentary Pharmacology &Amp; Therapeutics

View full text Add to dashboard Cite

Aliment Pharmacol Ther 2011; 34: 544–554 Summary Background Low thiopurine‐methyl‐transferase (TPMT) activity and high 6‐thioguanine‐nucleotide (6TGN) concentrations have been linked to therapeutic success in inflammatory bowel disease patients treated with thiopurines; however, this has not been implemented in clinical practice. Aim To identify a therapeutic threshold value for TPMT or 6TGN concentrations, and their capability to predict treatment safety and efficacy. Methods Prospective multicentre study including steroid‐resistant/dependent patients starting thiopurines. The TPMT activity was determined at inclusion (>5 U/mL required). Azathioprine metabolites [6TGN, 6‐methyl‐mercaptopurine ribonucleotides (6MMP), and 6TGN/6MMP and 6TGN/TPMT ratios] were periodically monitored during steroid tapering and after withdrawal for 6 months or until a new flare occurred. Results A total of 113 patients were analysed (62% clinical response). Areas under the receiver operating characteristic (ROC) curve (AUC) relating clinical response and metabolite levels at 2, 4 and 6 months after steroid withdrawal were less than 0.7. The AUCs relating final response and initial TPMT activity or metabolite concentrations at 2, 4, 8 and 16 weeks after starting thiopurines were less than 0.7. No cut‐off point with worthwhile sensitivity/specificity was found. Eight (7%) patients developed thiopurine‐related toxicity that could not be linked to TPMT activity or 6TGN levels. Conclusions Our results do not support determination of TPMT activity or 6TGN concentrations to predict treatment outcome, and no useful serum metabolites threshold value to adjust the drug’s dose was identified.

show abstract

Section: Discussionmentioning

confidence: 99%

Thiopurine methyl-transferase activity and azathioprine metabolite concentrations do not predict clinical outcome in thiopurine-treated inflammatory bowel disease patients

González-Lama

Bermejo²,

López-Sanromán

et al. 2011

Alimentary Pharmacology &Amp; Therapeutics

View full text Add to dashboard Cite

show abstract

“…In all centres, tioguanine metabolites were determined in red blood cells (RBC) using a method by Dervieux and Boulieu . Due to a lack of standardised operating procedures for measuring thiopurine metabolites, we considered that analysed 6‐TGN concentrations might differ between the three hospital laboratories .…”

Section: Methodsmentioning

confidence: 99%

Sustained effectiveness, safety and therapeutic drug monitoring of tioguanine in a cohort of 274 IBD patients intolerant for conventional therapies

Simsek

Deben

Horjus

et al. 2019

Aliment Pharmacol Ther

View full text Add to dashboard Cite

Summary Background Tioguanine (or thioguanine) is an alternative drug for IBD patients who fail prior conventional immunomodulating therapy. Aim To report effectiveness, safety and therapeutic drug monitoring in a cohort of patients with prolonged tioguanine maintenance therapy. Methods In this nationwide, multicentre study, medical records of tioguanine‐ using IBD patients were retrospectively reviewed. Response to therapy was defined as clinical effectiveness without (re)initiation of corticosteroids, concurrent biological therapy or surgical intervention. All adverse events that occurred during the follow‐up were listed and graded according to the common terminology criteria (CTC). Results Two hundred and seventy‐four patients (female 63%, Crohn's disease in 68%) were included with median treatment duration of 51 months, 1567 patient‐years of follow‐up and median 20 mg/d tioguanine dosage. Tioguanine was tolerated in 79%, clinical effectiveness at 6 months was documented in 66% and sustained clinical effectiveness during 12 months in 51% of patients. Forty‐one per cent of patients developed adverse events: 5% were graded as severe. Adverse events comprised infection requiring hospitalisation in three and skin cancer in eight patients (two melanomas). Asymptomatic nodular regenerative hyperplasia of the liver occurred in two out of 52 patients with liver biopsies (3.8%) and portal hypertension in three whereof one potentially associated with tioguanine (0.4%). Clinical effectiveness was correlated with 6‐thioguanine nucleotide threshold concentrations >682 pmol/8×108 RBC (P < 0.05). Conclusions Long‐term tioguanine therapy for at least 12 months was effective in 51% and well tolerated as a maintenance treatment for IBD in about 70% of patients. Adverse events were common, but mainly mild or moderate. 6‐Thioguanine nucleotide threshold concentration ≥ 700 pmol/8×108 RBC is proposed as target level with higher odds for clinical effectiveness.

show abstract

“…In patients on thiopurines treatment, analysis of thiopurine metabolites was carried out. The simultaneous determination in erythrocytes of 6‐tioguanine nucleotides (6‐TGN) and 6‐methylmercaptopurine (6‐MMP) was performed by the HPLC assay described elsewhere 30 with minor modifications. Plasma was decanted and the leucocytes and the upper layer of erythrocytes were removed.…”

Section: Methodsmentioning

confidence: 99%

Prospective study of the effects of concomitant medications on thiopurine metabolism in inflammatory bowel disease

Sostegni¹,

Canaparo²,

Serpe³

et al. 2009

Aliment Pharmacol Ther

View full text Add to dashboard Cite

show abstract

Simultaneous determination of 6-thioguanine and methyl 6-mercaptopurine nucleotides of azathioprine in red blood cells by HPLC

Cited by 188 publications

References 8 publications

Thiopurine methyl-transferase activity and azathioprine metabolite concentrations do not predict clinical outcome in thiopurine-treated inflammatory bowel disease patients

Thiopurine methyl-transferase activity and azathioprine metabolite concentrations do not predict clinical outcome in thiopurine-treated inflammatory bowel disease patients

Sustained effectiveness, safety and therapeutic drug monitoring of tioguanine in a cohort of 274 IBD patients intolerant for conventional therapies

Prospective study of the effects of concomitant medications on thiopurine metabolism in inflammatory bowel disease

Contact Info

Product

Resources

About