PharmGKB summary: methotrexate pathway.
PharmGKB summary: methotrexate pathway.
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DOI：
10.1097/fpc.0b013e328343dd93
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发表时间：
2011-10
影响因子：
2.6
通讯作者：
Altman RB
中科院分区：
文献类型：
--
作者：
Mikkelsen TS;Thorn CF;Yang JJ;Ulrich CM;French D;Zaza G;Dunnenberger HM;Marsh S;McLeod HL;Giacomini K;Becker ML;Gaedigk R;Leeder JS;Kager L;Relling MV;Evans W;Klein TE;Altman RB
甲氨蝶呤是一种叶酸类似物，用于治疗癌症（如急性淋巴细胞白血病、非霍奇金淋巴瘤、骨肉瘤和结肠癌）和自身免疫性疾病（如类风湿性关节炎、克罗恩病和银屑病）。在自身免疫性疾病的治疗中，甲氨蝶呤通常口服或皮下给药，而在癌症治疗中，它可以口服、肌内、鞘内注射或静脉输注（高达12 g/m2）[1-3]。甲氨蝶呤的药代动力学和药效学显示出较大的患者间变异性，无论给药途径或治疗的疾病如何[4-6]。本研究的目的是提供甲氨蝶呤药物基因组学的介绍，显示PharmGKB甲氨蝶呤途径中的候选基因（图1），重要变量（表1和2），讨论了关键知识，并指出了更深入的资源。甲氨蝶呤药代动力学的个体间差异可以部分解释为与甲氨蝶呤亲和力的膜转运蛋白的遗传变异[4，89]。在胃肠道中，甲氨蝶呤通过还原叶酸载体（SLC 19 A1）介导的主动转运吸收，也可能通过肠上皮细胞顶膜处的质子偶联叶酸转运蛋白SLC 46 A1（HCP 1，PCFT）进行吸收[90]。此外，口服给药后甲氨蝶呤的生物利用度可能受到ABC转运蛋白的影响，ABC转运蛋白可将甲氨蝶呤移出肠细胞并返回肠道（ABCC 2、ABCB 1和ABCG 2）或进入血液（ABCC 1和ABCC 3）[91-93]。甲氨蝶呤的全身清除主要通过肾小球过滤和近端肾小管细胞的主动分泌发生。几种肾转运蛋白对甲氨蝶呤具有亲和力（SLC 22 A6、SLC 22 A8、SLC 19 A1，
Methotrexate is a folate analog that is used in the treatment of cancers (eg acute lymphoblastic leukemia, non-Hodgkin lymphoma, osteosarcoma, and colon cancer) and autoimmune diseases (eg rheumatoid arthritis, Crohn’s disease, and psoriasis). In the treatment of autoimmune diseases, methotrexate is usually administrated orally or subcutaneously, whereas in the cancer treatment, it can be given orally, intramuscularly, as intrathecal injections, or as intravenous infusions (up to 12g/m2)[1–3]. The pharmacokinetics and pharmacodynamics of methotrexate show large interpatient variability regardless of the route of administration or disease being treated [4–6]. The goal of this study is to provide an introduction to methotrexate pharmacogenomics, showing the candidate genes in the PharmGKB methotrexate pathway (Fig. 1), important variants (Tables 1 and 2), discussing key knowledge, and pointing to more in-depth resources.The interindividual variability in methotrexate pharmacokinetics can be explained partially by genetic variations in membrane transporter proteins with an affinity for methotrexate [4, 89]. In the gastrointestinal tract, methotrexate is absorbed through active transport mediated by the reduced folate carrier (SLC19A1) and possibly also by the proton-coupled folate transporter SLC46A1 (HCP1, PCFT) at the apical membrane of enterocytes [90]. Furthermore, the bioavailability of methotrexate after oral dosing may be affected by ABC transporters, which can move methotrexate out of the enterocytes and back into the intestinal tract (ABCC2, ABCB1, and ABCG2) or into the blood (ABCC1 and ABCC3)[91–93]. Systemic clearance of methotrexate happens primarily through renal glomerular filtration and active secretion over the proximal tubular cells. Several renal transporter proteins have an affinity for methotrexate (SLC22A6, SLC22A8, SLC19A1,