转运蛋白与药物代谢动力学、多药耐药关系的研究进展

目的介绍近年来转运蛋白与药物代谢动力学、多药耐药关系的最新进展。方法依据文献对转运蛋白与药物代谢动力学、多药耐药关系的研究进展进行综述。结果转运蛋白影响药代过程,反复接触同一药物则可能产生多药耐药,如何有效利用转运蛋白的各种特性研发药物成为热点。结论深入地分析转运蛋白的理化特性、药物代谢动力学过程和多药耐药,从而设计出更安全有效的药物。     

药物引起的心肌损害

某些对心脏有毒性的药物可以招致猝死或不可逆性心肌损害。这类药物中,以抗恶性肿瘤药、抗精神失常药居多。这是鉴于原发病的特点,多数需要大量或长期给药的结果。1 抗恶性肿瘤药物引起的心肌损害已经知道产生心肌损害的抗恶性肿瘤药物有:蒽环类药物、环磷酰胺、5-Fu、丝裂霉素等。发现蒽环类药物对心脏毒性频度最高。蒽环类药物对淋巴瘤、白血病、肺癌、乳癌、骨肉瘤、膀胱癌等有效。临床使用的有阿霉素、柔红霉素、阿克拉霉素三种药物。作为对心脏没有毒性的衍生物匹来霉素、表阿霉素等正在研制。被广泛使用的阿霉素的心脏毒性广为人知。目前,单用本药引起心功能不全病例已有减少,是重要的基础药物。另外,在阿     

几种表面活性剂的细胞毒性研究

目的:研究不同的表面活性剂的细胞毒性,从而筛选出低毒性的表面活性剂,为以后的进一步研究表面活性剂逆转肿瘤细胞的多药耐药提供基础。方法:采用MTT(四甲基偶氮唑盐)检测方法,研究9种不同类型表面活性剂对肿瘤细胞K562／S及其多药耐药株K562／A02的细胞毒性,并比较同一表面活性剂对药物敏感肿瘤细胞和多药耐药肿瘤细胞的细胞毒性之间的差别。结果:非离子表面活性剂对肿瘤细胞K562／S及其多药耐药细胞K562／A02的IC50在10-1mg·ml-1数量级,阳离子及阴离子表面活性剂的IC50为10-3 mg·ml-1数量级。结论:非离子表面活性剂的细胞毒性最小,阴离子表面活性剂次之,阳离子表面活性剂的细胞毒性最大,同一表面活性剂对药物敏感肿瘤细胞及其肿瘤耐药细胞的细胞毒性没有差异,表明表面活性剂对肿瘤细胞多药耐药的逆转不是由其本身的细胞毒性引起的。     

抗肿瘤纳米制剂药代动力学评价的研究进展

抗肿瘤药物水溶性差、药代动力学行为不理想等特征在临床应用中严重影响疗效。抗肿瘤纳米制剂的开发可以实现药物増溶的目的,能够改善抗肿瘤药物的药代动力学行为,具有良好的应用前景。本文综述了抗肿瘤纳米制剂的研究现状,分别从整体和细胞水平介绍其药代动力学行为特征,探讨抗肿瘤纳米制剂发挥优势可能的作用机制。     

生物技术药物的药代动力学研究近况

以3类生物技术药物，即蛋白多肽类药物、核酸药物和单克隆抗体类药物为例，综述近年来生物技术药物的药代动力学研究进展，介绍这3类药物药代动力学的特性和研究分析方法及其特点。生物技术药物因其疗效好，副作用小，应用范围广泛，已成为新药研究开发的新宠，也将是最活跃和发展最迅速的领域，因此其药代动力学研究的发展备受关注。     

多粘菌素用法及药代动力学研究进展

多粘菌素是一种阳离子多肽类抗生素,在1950年代首次用于临床,但在1970年代由于肾毒性和神经毒性而被基本弃用.最近,多重耐药革兰阴性病原体的流行,迫使多粘菌素再次成为临床治疗多重耐药革兰阴性菌的最后一线药物手段.临床证据表明,多粘菌素B由于以其活性形式给药,其药代动力学变异较小,主要通过非肾脏途径消除,因此肾功能损害患者无需调整用药剂量.而CMS可通过肾小球滤过和肾小管排泄迅速清除,20％～25％自发水解为粘菌素.但是不同患者具有其特殊的病理生理状态,药代动力学参数与健康志愿者间存在较大差异,按照健康人体的药代动力学参数指导用药,可能会导致药物剂量不足或剂量过大而增加毒副作用.     

P-糖蛋白与多药耐药的关系

肿瘤多药耐药(M ultidrug R esistance,M D R)是指一种药物作用于肿瘤使之产生耐药性后,该肿瘤对未接触过的、结构无关、机制各异的多种抗肿瘤药也具有交叉耐药性的现象。耐药的产生取决于作用靶点部位的药物浓度、靶点本身的量和质以及靶点和药物之间的相互作用,而M D R产生的机制比较复杂,涉及到药物的外排增加和亚细胞分布改变;药物作用靶标如拓扑异构酶改变;代谢转化改变;损伤修复增强;凋亡相关通路改变;细胞增殖速率变化;体内药代动力学因素等。这些机制常可同时存在,但以一种为主,且不同机制间常相互影响。本文就近年来M D R产生…     

N末端脑钠肽前体和血浆肌钙蛋白Ⅰ监测蒽环类药物所致早期心脏毒性的临床意义

<正>蒽环类药物(anthracycline)主要包括阿霉素、表阿霉素、吡喃阿霉素、柔红霉素和米托蒽醌等,广泛地用于治疗血液系统恶性肿瘤和实体肿瘤,是乳腺癌辅助化疗方案的首选药物。但是蒽环类药物存在心脏毒性,包括急性、慢性和迟发性毒性。初次使用蒽环类药物即可造成心脏损伤,随着药物累积剂量的增加毒性愈加明显且不可逆。因此早期监测蒽环类药物引起的心脏毒性并及早干预显得尤为重要。本研究监测应用蒽环类药物化疗前后     

基于药代动力学方法支持的万古霉素个体化给药现状

万古霉素是耐甲氧西林金黄色葡萄球菌等耐药阳性球菌的一线治疗药物,其具有治疗窗窄、个体差异大、肾毒性等特点,因此有必要进行治疗药物监测及基于药代动力学(PK)方法进行个体化给药。近年有数篇万古霉素个体化给药相关研究发表,本文综述了基于PK的万古霉素个体化给药方法研究,旨在为临床实践提供参考。     

肿瘤多药耐药模型的建立与评价方法

开发多药耐药肿瘤的细胞模型和动物模型对于其相关基础研究和药物评价意义重大。综述了肿瘤多药耐药模型的建模方法,分别对细胞模型和荷瘤动物模型的建立类型、各自特点、评价手段及研究意义等进行了分析和总结。为建立优势肿瘤多药耐药模型、优化现有抗肿瘤药物评价方法提供参考,有助于阐明多药耐药相关机制,并为临床用药提供指导。     

Relevance of multidrug resistance proteins for intestinal drug absorption in vitro and in vivo

Multidrug resistance proteins (p-glycoprotein and mrps) are becoming increasingly important to explain the pharmacokinetics and action of drugs. Located in epithelial and endothelial cells of the gastrointestinal tract, liver, kidney, blood brain barrier, choroid plexus and other organs, they are critical determinants for the movement of a large number of commonly prescribed drugs across cellular barriers. Here we provide a brief overview of the role of multidrug resistance proteins in drug absorption from the gastrointestinal tract. We address the different types of multidrug resistance proteins involved, describe experimental models to study the influence of these proteins on transcellular transport and discuss the impact of multidrug resistance proteins on overall drug bioavailability in vivo.     

Increased toxicity of anthracycline antibiotics induced by calcium entry blockers in cultured cardiomyocytes

Calcium channel blocking drugs have been reported to reduce survival rate of laboratory animals treated with cardiotoxic antitumor anthracyclines. In order to elucidate the mechanisms of this drug interaction, cell toxicity of the anthracyclines, doxorubicin and daunorubicin, was evaluated in primary cultures of cardiac myocytes isolated from neonatal rats. Low concentrations of extracellular calcium ([Ca2+]0) and addition of calcium entry blockers (nifedipine or flunarizine) potentiated myocardial toxicity of anthracyclines as assessed by the release of lactate dehydrogenase from the cells. Accumulation of anthracyclines in the cardiomyocytes was increased by calcium entry blockers (nifedipine, flunarizine, and verapamil) and by low [Ca2+]0; efflux of [3H]daunorubicin from myocardial cells was inhibited by nifedipine. At a dose that exerts only modest calcium channel activity, R-verapamil failed to affect doxorubicin accumulation in cardiomyocytes, whereas the calcium channel activator, (+/-)-Bay K-8644, reduced the retention of anthracyclines; the calcium channel activity is thus required in order to increase the accumulation of anthracyclines in myocardial cells. Calcium channel blockers are also known to increase intracellular retention and toxicity of chemotherapeutic drugs in multidrug resistant tumor cells by inhibiting the efflux of cytotoxic agents from cells; however, the ability of the interacting drugs to inhibit the efflux of chemotherapeutic agents from tumor cells is not dependent on the calcium channel blocking activity. Therefore, the mechanism(s) by which calcium channel blocking drugs increase the accumulation of anthracyclines in resistant tumor cells and myocardial cells may be different. In accordance with previous investigations, the present in vitro study confirmed that anthracycline-induced cardiotoxicity may be potentiated by calcium channel blocking drugs. This indicates that, in the association of antineoplastic drugs with agents that reverse multidrug resistance, the potential exists for enhanced damage of normal cells and tissues; further studies are needed to evaluate the relevance of this adverse interaction.     

Pharmacokinetic and pharmacodynamic implications of P-glycoprotein modulation.

P-glycoprotein (P-gp) is a cell membrane-associated protein that transports a variety of drug substrates. Although P-gp has been studied extensively as a mediator of multidrug resistance in cancer, only recently has the role of P-gp expressed in normal tissues as a determinant of drug pharmacokinetics and pharmacodynamics been examined. P-glycoprotein is present in organ systems that influence drug absorption (intestine), distribution to site of action (central nervous system and leukocytes), and elimination (liver and kidney), as well as several other tissues. Many marketed drugs inhibit P-gp function, and several compounds are under development as P-gp inhibitors. Similarly, numerous drugs can induce P-gp expression. While P-gp induction does not have a therapeutic role, P-gp inhibition is an attractive therapeutic approach to reverse multidrug resistance. Clinicians should recognize that P-gp induction or inhibition may have a substantial effect on the pharmacokinetics and pharmacodynamics of concomitantly administered drugs that are substrates for this transporter.     

New light on multidrug binding by an ATP-binding-cassette transporter

ATP-binding-cassette (ABC) multidrug transporters confer multidrug resistance to pathogenic microorganisms and human tumour cells by mediating the extrusion of structurally unrelated chemotherapeutic drugs from the cell. The molecular basis by which ABC multidrug transporters bind and transport drugs is far from clear. Genetic analyses during the past 14 years reveal that the replacement of many individual amino acids in mammalian multidrug resistance P-glycoproteins can affect cellular resistance to drugs, but these studies have failed to identify specific regions in the primary amino acid sequence that are part of a defined drug-binding pocket. The recent publication of an X-ray crystallographic structure of the bacterial P-glycoprotein homologue MsbA and an MsbA-based homology model of human P-glycoprotein creates an opportunity to compare the original mutagenesis data with the three-dimensional structures of transporters. Our comparisons reveal that mutations that alter specificity are present in three-dimensional 'hotspot' regions in the membrane domains of P-glycoprotein.     

Transporter-mediated drug-drug interactions

Drug-drug interactions are a serious clinical issue. An important mechanism underlying drug-drug interactions is induction or inhibition of drug transporters that mediate the cellular uptake and efflux of xenobiotics. Especially drug transporters of the small intestine, liver and kidney are major determinants of the pharmacokinetic profile of drugs. Transporter-mediated drug-drug interactions in these three organs can considerably influence the pharmacokinetics and clinical effects of drugs. In this article, we focus on probe drugs lacking significant metabolism to highlight mechanisms of interactions of selected intestinal, hepatic and renal drug transporters (e.g., organic anion transporting polypeptide [OATP] 1A2, OATP2B1, OATP1B1, OATP1B3, P-gp, organic anion transporter [OAT] 1, OAT3, breast cancer resistance protein [BCRP], organic cation transporter [OCT] 2 and multidrug and toxin extrusion protein [MATE] 1). Genotype-dependent drug-drug interactions are also discussed.     

Impact of genetic polymorphisms of transporters on the pharmacokinetic, pharmacodynamic and toxicological properties of anionic drugs

As the importance of drug transporters in the clinical pharmacokinetics of drugs is recognized, genetic polymorphisms of drug transporters have emerged as one of the determinant factors to produce the inter-individual variability of pharmacokinetics. Many clinical studies have shown the influence of genetic polymorphisms of drug transporters on the pharmacokinetics and subsequent pharmacological and toxicological effects of drugs. The functional change in a transporter in clearance organs such as liver and kidney affects the drug concentration in the blood circulation, while that in the pharmacological or toxicological target can alter the local concentration at the target sites without changing its plasma concentration. As for the transporters for organic anions, some single nucleotide polymorphisms (SNPs) or haplotypes occurring with high frequency in organic anion transporting polypeptide (OATP) 1B1, multidrug resistance 1 (MDR1), and breast cancer resistance protein (BCRP) have been extensively investigated in both human clinical studies and in vitro functional assays. We introduce some examples showing the relationship between haplotypes in transporters and pharmacokinetics and pharmacological effects of drugs. We also discuss how to predict the effect of functional changes in drug transporters caused by genetic polymorphisms on the pharmacokinetics of drugs from in vitro data.     

Characterization of anthracenediones and their photoaffinity analogs

In an attempt to overcome the cardiotoxicity and cross-resistance problems caused by the anticancer drugs anthracyclines and anthracenediones during chemotherapy, we have developed a series of aza-anthracenedione compounds by modifying the chromophore and the side arms of anthracyclines and anthracenediones. One of these aza-anthracenediones, 6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione (BBR 2778), which is currently under phase II clinical trials, showed remarkable antitumor activity and appeared to lack a cardiotoxic effect in preclinical studies. However, it was still cross-resistant against multidrug resistance (MDR) cells expressing P-glycoprotein (P-gp). In contrast, another aza-anthracenedione, 6,9-bis[[2-(dimethylamino)ethyl]amino]benzo[g]isoquinoline-5,10-dione, which has side arm structures different from those of BBR 2778, was highly active against MDR cells. In this study, BBR 2778, BBR 2378, and an anthracenedione compound, 1,4-bis[(2-aminoethyl)amino]-5,8-dimethyl-9,10-anthracenedione, were used to assess the relationship between the chemical structures of these drugs and their interactions with DNA and P-gp. In addition, the biological and pharmacological influences of photoaffinity labeling were also studied for BBR 2778 and DEH. As the results indicate, the photolabeled analogs of BBR 2778 and DEH were less DNA-reactive and less cytotoxic. The more lipophilic compound, BBR 2378, and the photolabeled analogs of BBR 2778 and DEH inhibited P-gp labeling by azidopine better than did the more hydrophilic parental compounds. These studies suggested that the DNA binding affinity of BBR 2778 and DEH could be important in determining their cytotoxicity, and that the chemical structure of the side arms and the lipophilicity of these drugs are critical in determining their cross-resistance.     

Resistance mechanisms in murine tumors with acquired multidrug resistance.

Mechanisms of multidrug resistance were studied in murine leukemia (L 1210) and sarcoma (Sa 180) tumors after pretreatment with anthracyclines in vivo. Despite identical pretreatment protocols, a considerable difference in the level of resistance between L 1210 and Sa 180 tumors was noted (for doxorubicin: 45-fold versus 340-fold; for daunorubicin: 51-fold versus 275-fold). However, no difference in mdr 1 gene-amplification and the overexpression of mdr 1-RNA or P-glycoprotein was demonstrated. None of these parameters did increase by further treatment with a higher concentration of anthracyclines. Resistant sublines of Sa 180 revealed an overexpression of glutathione S-transferase-pi (GST-pi) in comparison to the parental line, whereas in sensitive and resistant sublines of L 1210 tumors the expression of GST-pi was similar. In order to study whether trifluoperazine can reverse the P-glycoprotein mediated component of multidrug resistance, trifluoperazine and doxorubicin were tested in vitro in L 1210 and Sa 180 cells. In contrast to the complete reversal of resistance in L 1210 tumors, resistance in Sa 180 was only partly circumvented. However, by buthionine sulfoximine treatment, the toxicity of multidrug resistant Sa 180 tumors could be increased. It was possible to reverse the resistance of Sa 180 tumors completely by trifluoperazine plus buthionine sulfoximine. Thus, multidrug-resistant Sa 180 tumors express different defense mechanisms whereas L 1210 tumors express only one defense mechanism (P-glycoprotein).     

New therapeutic options for chemotherapy-resistant metastatic breast cancer: the epothilones

When taxanes were introduced as anticancer agents some 20 years ago, their broad spectrum of activity was striking and engendered renewed hope for cancer patients. However, they were not without their problems, including a susceptibility to drug resistance caused by the drug efflux pump protein, P-glycoprotein. The epothilones are a new class of chemotherapeutic agents that have a mechanism of action similar enough to the taxanes to retain their broad spectrum of activity, but different enough to escape the multidrug resistance caused by P-glycoprotein. These properties are especially promising for patients with metastatic breast cancer who have run out of therapeutic options as a result of multidrug resistance. Ixabepilone, a semi-synthetic analogue of epothilone B, has recently been granted US FDA approval for the treatment of chemotherapy-resistant advanced breast cancer. Approval was based on results from a phase III study of ixabepilone in combination with capecitabine, as well as phase II studies of ixabepilone monotherapy. Significantly prolonged progression-free survival and increased objective response rates were demonstrated in the phase III study when ixabepilone was administered in combination with capecitabine compared with capecitabine alone. The phase II trials demonstrated robust antitumour activity with single-agent ixabepilone in women with metastatic breast cancer that was resistant to taxanes, anthracyclines and capecitabine. Early data from phase I trials of KOS-1584 and sagopilone are positive and suggest that these drugs may also develop into useful chemotherapeutic agents. Significant, but manageable, toxicities have been observed with the epothilones. In particular, neuropathy has led to the uneven and slower than expected clinical development of ixabepilone as optimal administration regimens were established. Some differences in tolerability profiles exist between the different analogues. Overall, it is expected that the epothilones will play an important role in the treatment of breast cancer and other tumour types.