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

被引：69

作者：

Gonzalez-Lama, Y. ^{[1
,2
,3
,4
]}

Bermejo, F. ^{[5
]}

Lopez-Sanroman, A. ^{[6
]}

Garcia-Sanchez, V. ^{[7
]}

Esteve, M. ^{[8
]}

Cabriada, J. L. ^{[9
]}

McNicholl, A. G. ^{[1
,2
,3
]}

Pajares, R. ^{[10
]}

Casellas, F. ^{[4
,11
]}

Merino, O. ^{[12
]}

Carpio, D. ^{[13
]}

Vera, M. I. ^{[3
]}

Munoz, C. ^{[14
]}

Calvo, M. ^{[3
]}

Benito, L. M. ^{[15
]}

Bujanda, L. ^{[4
,16
]}

Garcia-Fernandez, F. J. ^{[17
]}

Ricart, E. ^{[18
]}

Ginard, D. ^{[19
]}

Velasco, M. ^{[1
]}

Carneros, J. A. ^{[5
]}

Mancenido, N. ^{[10
]}

Calvo, M. ^{[3
]}

Algaba, A. ^{[5
]}

Froilan, C. ^{[10
]}

Cara, C. ^{[20
]}

Mate, J. ^{[1
,2
,4
]}

Abreu, L. ^{[3
]}

Gisbert, J. P. ^{[1
,2
,4
]}

机构：

[1] Hosp La Princesa, Madrid, Spain

[2] Inst Invest Sanitaria Princesa IP, Madrid, Spain

[3] Hosp Puerta Hierro, Madrid, Spain

[4] CIBEREHD, Madrid, Spain

[5] Hosp Univ Fuenlabrada, Madrid, Spain

[6] Hosp Ramon & Cajal, Madrid, Spain

[7] Hosp Reina Sofia, Cordoba, Spain

[8] Hosp Mutua Terrasa, Barcelona, Spain

[9] Hosp Galdakao, Vizcaya, Spain

[10] Hosp La Paz, Madrid, Spain

[11] Hosp Valle De Hebron, Barcelona, Spain

[12] Hosp Cruces, Bilbao, Spain

[13] Hosp Montecelo, Pontevedra, Spain

[14] Hosp San Eloy, Vizcaya, Spain

[15] Hosp Virgen del Toro, Menorca, Spain

[16] Hosp Donostia, San Sebastian, Spain

[17] Hosp San Juan de Dios del Aljarafe, Seville, Spain

[18] Hosp Clin Barcelona, Barcelona, Spain

[19] Hosp Son Duerta, Mallorca, Spain

[20] UCB Pharma, Madrid, Spain

来源：

ALIMENTARY PHARMACOLOGY & THERAPEUTICS | 2011年 / 34卷 / 05期

关键词：

METHYLTRANSFERASE TPMT ACTIVITY; RED-BLOOD-CELLS; LIQUID-CHROMATOGRAPHY; CROHN DISEASE; LONG-TERM; 6-MERCAPTOPURINE; 6-THIOGUANINE; THERAPY; PHARMACOGENETICS; MERCAPTOPURINE;

D O I：

10.1111/j.1365-2036.2011.04756.x

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

100201 [内科学];

摘要：

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.

引用

页码：544 / 554

页数：11

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