Impact of ABCC2 polymorphisms on high-dose methotrexate pharmacokinetics in patients with lymphoid malignancy

被引：44

作者：

Simon, N. ^{[1
]}

Marsot, A. ^{[1
]}

Villard, E. ^{[2
]}

Choquet, S. ^{[3
]}

Khe, H-X ^{[4
]}

Zahr, N. ^{[5
]}

Lechat, P. ^{[5
]}

Leblond, V. ^{[3
]}

Hulot, J-S ^{[2
,5
]}

机构：

[1] Aix Marseille Univ, Serv Pharmacol Med & Clin, AP HM, Hop Timone, Marseille, France

[2] Univ Paris 06, UMR S 956, Paris, France

[3] Pitie Salpetriere Univ Hosp, Dept Haematol, AP HP, Paris, France

[4] Pitie Salpetriere Univ Hosp, Dept Neurol, AP HP, Paris, France

[5] Pitie Salpetriere Univ Hosp, AP HP, Dept Pharmacol, Paris, France

来源：

PHARMACOGENOMICS JOURNAL | 2013年 / 13卷 / 06期

关键词：

multidrug-resistance-associated proteins; methotrexate; polymorphisms; lymphoid malignancy; pharmacokinetics; ACUTE LYMPHOBLASTIC-LEUKEMIA; METABOLITE; 7-HYDROXYMETHOTREXATE; BAYESIAN-ESTIMATION; CHILDREN; EXPRESSION; MRP2; ELIMINATION; PROTEIN; YOUNG; OSTEOSARCOMA;

D O I：

10.1038/tpj.2012.37

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Human multidrug resistance-related protein 2 (MRP2, encoded by ABCC2) is involved in the transport of anionic drugs such as methotrexate (MTX). We prospectively investigated the influence of four common ABCC2 genetic variants (rs717620, rs2273697, rs8187694 and rs8187710) on MTX pharmacokinetics parameters. MTX concentrations were monitored in 50 patients with lymphoid malignancy (27 males; mean age: 53 +/- 17 years) receiving high-dose MTX (5.13 +/- 1.88 g m(-2) in a 4-h perfusion). The population pharmacokinetics modelling showed that ABCC2 - 24T allele (rs717620) had a combined influence on both MTX elimination and distribution. The MTX clearance and distribution volume were significantly higher in carriers of at least one copy of the - 24T allele as compared with noncarriers: 8.6 +/- 2.2 vs 6.7 +/- 2.5 l h(-1), P<0.01 and 30.7 +/- 7.7 vs 22.1 +/- 8.8 l, P<0.001, respectively. Consequently, - 24T allele carriers were more prone to reach MTX nontoxic levels, 48 h after administration.

引用

页码：507 / 513

页数：7

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