Aix-Marseille université, Service de Pharmacologie Médicale et Clinique, AP-HM, Hôpital de la Timone, Marseille, France.
Pharmacogenomics J. 2013 Dec;13(6):507-13. doi: 10.1038/tpj.2012.37. Epub 2012 Oct 16.
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.
人多药耐药相关蛋白 2（MRP2，由 ABCC2 编码）参与阴离子药物如甲氨蝶呤（MTX）的转运。我们前瞻性研究了四个常见的 ABCC2 遗传变异（rs717620、rs2273697、rs8187694 和 rs8187710）对 MTX 药代动力学参数的影响。在接受高剂量 MTX（5.13±1.88 g·m-2，4 小时灌注）的 50 例淋巴恶性肿瘤患者（27 名男性；平均年龄：53±17 岁）中监测 MTX 浓度。群体药代动力学模型表明，ABCC2-24T 等位基因（rs717620）对 MTX 的消除和分布均有综合影响。与非携带者相比，至少携带一个-24T 等位基因的患者 MTX 清除率和分布容积显著更高：8.6±2.2 比 6.7±2.5 l·h-1，P<0.01；30.7±7.7 比 22.1±8.8 l，P<0.001。因此，携带-24T 等位基因的患者更倾向于在给药后 48 小时达到 MTX 无毒水平。
