转运体在药物胆汁排泄中的作用

目的:综述转运体在药物胆汁排泄中的作用。方法:以近几年国内外研究文献为基础,从转运体介导药物的胆汁排泄过程、介导药物胆汁排泄的转运体、药物相互作用、转运体的基因多态性等方面进行综述。结果:转运体对药物体内经胆汁排泄过程、临床用药安全性、用药后的个体差异等方面均存在影响。结论:随着对转运体认识的不断深入,其将在药物设计、临床合理用药、个体化治疗等方面发挥重要作用。     

肠道药物转运体及其研究方法

口服药物在肠道中的吸收是决定药物生物利用度的重要因素。肠道中有许多药物膜转运蛋白介导药物的吸收、分布、排泄及药物相互作用等。明确其转运机制有利于提高药物的安全性和有效性,从而指导临床合理用药。通过体内外方法预测药物经转运体在肠道中的转运情况。本文介绍了肠道内转运药物的主要膜转运蛋白,阐述了口服药物经肠道转运机制,概括了研究肠道药物转运体的主要研究方法,并对多种体内外转运体研究方法的优缺点进行了比较。     

有机阴离子转运多肽介导的药物相互作用研究进展

药物转运体介导的药物相互作用正日益受到人们的关注和重视,近年来的研究表明药物转运体对药物的吸收、分布和排出有着重要的作用。有机阴离子转运多肽是一类药物摄取转运体,其表达分布广泛,转运的内源性和外源性的底物众多,一些药物因抑制有机阴离子转运体而导致药物相互作用。本文综述了有机阴离子转运多肽家族不同成员的组织分布、结构特点以及其介导的药物相互作用的最新研究进展。     

基于转运体的中药毒性及药物相互作用研究进展

中药-药物的相互作用已成为药物毒性研究的热点。许多中药的活性成分或其提取物在体内的药效和毒性与转运体相关，转运体的表达或活性可明显影响中药在体内的药动学和生物活性。其中，基于转运体的马兜铃酸、雷公藤甲素等中药成分的肝、肾毒性的研究十分广泛，而中药对转运体的作用也会对其他药物的代谢产生影响从而发生药物的相互作用。主要基于转运体角度来概述中药毒性及对其他药物代谢的影响，对中药的毒性研究及临床上的合理用药具有指导意义。     

治疗心血管疾病的中药组分对转运体的调节作用研究进展

药物在肝脏代谢过程中除代谢酶参与外,药物转运体同样也起着举足轻重的作用。除他汀类、沙坦类等心血管系统化学药对转运体会产生影响外,近年来的研究表明,一些常用于治疗心血管系统疾病的中药组分亦会影响转运体的摄取外排功能,在与西药联合应用的过程中,可能会对介导西药的肝脏转运体产生影响,从而引起药动学改变而增加药品不良反应的发生。本文从治疗心血管系统疾病的常用中药组分对转运体的影响和与其他药物联用时可能发生的药物相互作用进行介绍,为临床提高药物治疗的有效性和安全性提供依据。     

HIV蛋白酶抑制剂的药代动力学相互作用

艾滋病的治疗是一个长期的过程,HIV蛋白酶抑制剂是此类病人最常选用的抗病毒药物。在治疗过程中,病人很可能患其它疾病,艾滋病自身也常伴随众多并发症,使得临床上不可避免的需要联用其它药物。由于HIV蛋白酶抑制剂对药物代谢酶和转运体有广泛的作用,因此探索HIV蛋白酶抑制剂的药物相互作用问题显得十分必要。本文重点从药代相互作用机制的角度综述了HIV蛋白酶抑制剂在临床上可能出现的药物相互作用方面的研究文献,包括HIV蛋白酶抑制剂与其它药物的相互作用以及蛋白酶抑制剂之间的相互作用及机制等,期望对于临床给药方案的设计和提高临床用药的安全性和有效性提供有价值的参考和借鉴。     

肾脏中转运体对核苷类抗病毒药物的转运作用

药物转运体在药物的药动学和药效学过程中发挥重要作用,而核苷类抗病毒药物与其他药物的相互作用主要基于肾小管膜上表达的转运体。本论文分别对肾脏中参与核苷类抗病毒药物转运的转运体,几种主要核苷类抗病毒药物以及它们之间相互作用的研究现状进行了综述。     

肝脏转运蛋白在药物肝胆转运中的作用

目的对肝脏转运蛋白在药物肝胆转运中的作用作一综述,为药物肝靶向提供依据。方法根据文献,从药物不良反应、药物的矢量转运、药物肝靶向性、药物之间相互作用4个方面阐述肝脏转运蛋白对药物肝胆排泄产生的影响。结果肝脏转运蛋白引起的药物矢量转运影响药物的肝脏摄取,药物肝靶向性影响药物的疗效,药物之间相互作用影响临床用药安全和不良反应。结论肝脏转运蛋白在药物肝胆转运中起到了重要的作用,它与药物在体内各组织分布、临床疗效均有密切的联系。     

类风湿关节炎患者转运蛋白基因多态性与甲氨蝶呤疗效及安全性的相关性研究进展

甲氨蝶呤是治疗类风湿关节炎应用最广泛的药物之一,其疗效及不良反应个体差异很大.本文介绍了人体甲氨蝶呤转运蛋白的结构和功能,并阐明其基因单核苷酸多态性可能对药物反应的个体差异.     

与核苷类化疗药相关的平衡型核苷转运体研究进展

核苷类化疗药物是临床上常见的抗癌药，用于多种癌症的治疗。此类药物需要通过细胞膜上的核苷转运体进入细胞，为提高药物的抗癌效果及研究癌细胞的耐药性机制，开发新的抗肿瘤药物，就需对核苷转运体及其跨膜转运机制有充分的认识。核苷转运体有两类，即平衡型核苷转运体（ENT）和浓度型核苷转运体（CNT）。其中ENT是主要的转运蛋白，分布广，底物选择性低，起着十分重要的作用。本文对ENT在细胞水平的研究进展作一综述。     

Pharmacokinetic drug–drug interactions with methotrexate in oncology

Methotrexate is an antifolate agent used in the treatment of various cancers and some autoimmune diseases. In oncology, methotrexate is frequently administered at a high dose (>1 g/m²) and comes with various procedures to reduce the occurrence of toxicity and particularly to ensure optimal renal elimination. Drug–drug interactions involving methotrexate are the origin of severe side effects owing to delayed elimination of the antifolate and, more rarely, of decreased efficacy in relation to suboptimal exposure. Most of these interactions are driven by membrane drug transporters whose activity/expression can be inhibited by the interacting medication. In the last 10 years, research on drug transporters has permitted retrospective identification of the molecular mechanisms underlying drug–drug interactions with methotrexate. This article summarizes reported drug–drug interactions involving methotrexate in clinical oncology with reference to the role of drug transporters that control the disposition of the antifolate agent.     

Pharmacokinetic drug-drug interactions with methotrexate in oncology

Methotrexate is an antifolate agent used in the treatment of various cancers and some autoimmune diseases. In oncology, methotrexate is frequently administered at a high dose (>1 g/m(2)) and comes with various procedures to reduce the occurrence of toxicity and particularly to ensure optimal renal elimination. Drug-drug interactions involving methotrexate are the origin of severe side effects owing to delayed elimination of the antifolate and, more rarely, of decreased efficacy in relation to suboptimal exposure. Most of these interactions are driven by membrane drug transporters whose activity/expression can be inhibited by the interacting medication. In the last 10 years, research on drug transporters has permitted retrospective identification of the molecular mechanisms underlying drug-drug interactions with methotrexate. This article summarizes reported drug-drug interactions involving methotrexate in clinical oncology with reference to the role of drug transporters that control the disposition of the antifolate agent.     

Characterization of the bile acid sensitive methotrexate carrier of rat liver cells

The chemotherapeutic agent methotrexate is widely used in tumor therapy for different forms of leukemia and for the therapy of arthritis. Methotrexate is eliminated from systemic blood circulation by the liver and its transport into hepatocytes is therefore described in detail in this paper. Methotrexate uptake is energy- and sodium-dependent. The K _m and the V _max are 23 μM and 36 pmol/mg protein min, respectively. The apparent activation energy (E _app) of methotrexate uptake (5 μM [³H]methotrexate) is 53.73 kJ/mol, which indicates an energy-dependent carrier-mediated process. Although methotrexate is a folate derivative, folate itself does not inhibit methotrexate uptake, whereas the reduced folates, dihydrofolate and tetrahydro-folate are weak uncompetitive inhibitors. In contrast, the bile acids taurocholate and cholate are effective competitive inhibitors of methotrexate uptake into hepatocytes. Further strong inhibitors are the loop diuretic bumetanide, the mycotoxin ochratoxin A and bromosulfophthalein. Because tumor patients develop drug resistance during methotrexate therapy, the uptake of methotrexate was tested in different hepatoma cell lines. In HepG2-cells and Reuber hepatoma Fao-cells the transport was non-existent or very small. However, the hepatocytoma fusion cell line HPCT-1E3, a hybrid cell line between primary rat hepatocytes and rat Reuber Fao-cells, shows an intermediate transport activity with a threefold increase of the methotrexate uptake. These results indicate the presence of a bile acid sensitive methotrexate carrier in hepatocytes which is absent in dedifferentiated hepatoma cells. The carrier differs from previously described transporters for the uptake of organic anions. Received: 26 October 1998 / Accepted: 25 January 1999     

质子泵抑制剂对大剂量甲氨蝶呤排泄延迟影响的研究现状

甲氨蝶呤为广谱抗叶酸类抗肿瘤药,大剂量甲氨蝶呤主要用于急性淋巴细胞白血病等肿瘤的治疗。临床实际工作中常合并使用质子泵抑制剂以预防甲氨蝶呤导致的胃肠道相关不良反应。有研究发现,合并使用质子泵抑制剂可能导致甲氨蝶呤血药浓度升高及延迟消除,但该结果仍存在争议。本文通过分析已报告的质子泵抑制剂与甲氨蝶呤相互作用有关的文献,并进行总结,对质子泵抑制剂与大剂量甲氨蝶呤排泄延迟的相关性及可能机制进行综述,提高甲氨蝶呤临床用药的合理性与安全性,降低药物不良反应的发生率。     

High-dose methotrexate during pregnancy: risk of malformations

Methotrexate is a cytotoxic and immunosuppressant drug mainly used in oncology and rheumatology. It is sometimes used at high doses to treat unruptured ectopic pregnancy. Methotrexate is teratogenic. Malformations reported after exposure in utero include: abnormalities of the skull and face, limb defects, failure of ossification, and congenital cardiopathy.The risk of malformations is probably dose-dependent and seems to be relatively low at the low weekly doses used in rheumatology. Three cases of malformations have been reported after failure of high-dose methotrexate in pregnancies that were misdiagnosed as ectopic. Two newborns had scoliosis, facial dysmorphism, limb malformations, or cardiopathy.The third newborn had minor malformations. In practice, high-dose methotrexate must only be used to treat ectopic pregnancy if the diagnosis has been confirmed. The woman should be informed of the risks to her unborn child in case of diagnostic error or treatment failure.     

Methotrexate blood level monitoring

Methotrexate toxicity can be avoided following high-dose therapy if certain management procedures are adhered to. These include careful fluid balance management and therapeutic drug level monitoring. A case is reported of an episode of methotrexate toxicity resulting from a fluid balance problem.     

甲氨蝶呤血药浓度与患者肝肾功能指标的相关性分析

目的：通过对22例次应用大剂量甲氨蝶呤（HD-MTX）化疗的急性淋巴细胞白血病（ALL）患者血药浓度监测、肝肾功能实验室检查数据进行分析总结,探讨 MTX 20 h 和44 h 血药浓度与 MTX 实验室肝肾功能指标之间的联系。方法对 ALL 患者应用 HD-MTX 化疗后20、44 h 进行血药浓度监测,患者 HD-MTX 化疗后进行血常规、肝肾功能、血糖、血脂、乳酸脱氢酶（LDH）等相关实验室检查,收集资料。采用 SPSS 19．0软件 Spearman 相关分析两变量之间的相关性。结果MTX 20、44 h 血药浓度与患者化疗后血肌酐（CRE）值呈正相关,而与血尿素氮（BUN）、尿酸（UA）值无关。MTX 20 h 血药浓度与患者化疗后血总胆红素（STB）、直接胆红素（DBIL）、谷丙转氨酶（ALT）、谷草转氨酶（AST）值均呈正相关,而44 h 血 MTX 浓度与 STB、DBIL、ALT、AST 值无相关性。结论MTX 20、44 h 血药浓度监测可以预测 MTX 化疗造成的肌酐升高型肾损害,而 MTX 20 h血药浓度监测对于 MTX 造成的肝损害也有一定的预测作用。     

Methotrexate-loxoprofen interaction: involvement of human organic anion transporters hOAT1 and hOAT3

Human organic anion transporters hOAT1 (SLC22A6) and hOAT3 (SLC22A8) are responsible for renal tubular secretion of an antifolic acid methotrexate, and are considered to be involved in drug interaction of methotrexate with nonsteroidal anti-inflammatory drugs (NSAIDs). In our hospital, a delay of methotrexate elimination was experienced in a patient with Hodgkin's disease, who took loxoprofen, a commonly used NSAID in Japan, which suggested a cause. In this study, we examined the drug interaction via hOAT1 and hOAT3, using Xenopus laevis oocytes. hOAT1 and hOAT3 mediated the methotrexate transport with low affinity (K(m) of 724.0 muM) and high affinity (K(m) of 17.2 muM), respectively. Loxoprofen and its trans-OH metabolite, an active major metabolite, markedly inhibited the methotrexate transport by both transporters. Their inhibition concentrations (IC(50)) were in the range of the therapeutic levels. These findings suggest that loxoprofen retards the elimination of methotrexate, at least in part, by inhibiting hOAT1 and hOAT3.     

The practical use of methotrexate in psoriasis

Psoriasis is an inflammatory disease of the skin associated with increased epidermal proliferation. The aetiology of the disease is unknown, but there seems to be a genetic predisposition. The goal of therapy in the treatment of psoriasis is to decrease the rate of epidermal proliferation and the underlying inflammation. Topical application of steroids and coal tar are the therapies of choice; however, for those patients with severe recalcitrant psoriasis who have failed conventional topical therapy methotrexate is an established alternative. The use of methotrexate in psoriasis is limited by its toxicity, and proper patient selection and close monitoring are essential in achieving good clinical response. The dosage used should be the lowest that will maintain the patient in comfort, not necessarily that which produces total resolution. Caution should be exercised when other agents are used concurrently with methotrexate, and possible drug interactions should be identified as these may influence the effectiveness and toxicity of methotrexate therapy. The common side effects associated with the use of methotrexate in psoriasis include bone marrow suppression, gastrointestinal symptoms and hepatotoxicity. Liver damage is a major concern in long term methotrexate therapy and thus liver biopsies are warranted to monitor any pathological changes. The drug is a known teratogen and should be avoided in pregnant patients. Women of childbearing age should use reliable contraception during therapy. Patients should be made aware of the signs and symptoms of methotrexate toxicity and inform their physicians promptly as most adverse effects can be ameliorated with appropriate dosage adjustment. Methotrexate will continue to play a major role in the treatment of psoriasis and it is thus important that it be used safely.