生理药代动力学软件模拟技术在药物研发和评价中的应用

生理药代动力学(physiologically-based pharmacokinetic, PBPK)软件模拟技术是通过计算机软件构建模型,模拟机体生理或病理环境,用以预测药物在体内的药代动力学行为(吸收、分布、代谢、排泄)。本综述概述了生理药代动力学模型的常用功能模块、在药物早期研发和新制剂研究、食物影响药物相互作用、儿童药物研究、吸入制剂开发及仿制药一致性评价等多方面的应用,并简要介绍了常用生理药代动力学软件的特点。讨论了生理药代动力学模型的当前挑战,包括模型建立的适用范围,模型准确性评估的判断标准等方面内容。     

聚合物纳米药物制剂生物分析方法及药动学研究进展

聚合物纳米药物制剂因其具有长循环、可降低免疫原性、不良反应小等优点,得到了越来越多的关注,已经成为纳米药物制剂研究的热点。然而,真正成功应用于临床的聚合物纳米药物制剂的数量非常少,药代动力学行为不理想是导致这一现象的主要原因之一。聚合物纳米制剂作为载药粒子进入体内之后,会释放出游离药物和聚合物辅料,游离药物是发挥药效的物质基础,而聚合物辅料则有可能会引起辅料-药物相互作用,因此,聚合物纳米药物制剂药代动力学研究的关注点不应该仅仅局限于游离药物本身,应该同时关注载药粒子、游离药物、聚合物辅料及其代谢物在体内的动态变化,这就为聚合物纳米药物制剂的生物分析方法提出了新的要求和挑战。基于此,本文简要介绍了聚合物纳米药物制剂的常用生物分析方法色谱分析法的特点及适用范围,概述了聚合物纳米药物制剂在体内的吸收、分布、代谢和排泄,希望能够为聚合物纳米药物制剂的药代动力学研究、安全性和有效性评价提供借鉴和参考。     

脂质体纳米药物制剂的生物分析方法及药代动力学研究进展

脂质体纳米药物制剂是一种被脂双分子层囊泡结构包裹的具有纳米尺度的新型药物制剂。脂质体作为药物递送载体,具备生物相容性良好、在体内可被生物降解以及定位靶向性强等优点。应用脂质体纳米药物递送系统,可在一定程度上改善某些药物在人体内的药代动力学行为及药效,减轻不良反应。脂质体纳米药物进入人体后,会释放游离型药物,因而体内会同时存在负载型脂质体纳米药物和游离型药物。负载型药物是药物的贮库,游离型药物与药物的药效和不良反应有关,因此,脂质体药代动力学研究应该同时关注负载型药物和游离型药物。游离药物、脂质体粒子及其材料的精准分析是脂质体体内定量研究的一个难点。本篇综述介绍了脂质体纳米药物的前处理方法,总结了脂质体纳米药物的生物分析方法及其药代动力学的研究进展,希望能够为脂质体纳米药物制剂的研究开发提供参考。     

羟氯喹及氯喹纳米制剂研究现状

羟氯喹和氯喹是一类具有抗肿瘤等多种良好生物活性的4-氨基喹啉衍生物类化合物,两药传统剂型存在的靶向性差、药物不良反应发生率高等缺点阻碍了其应用和发展。本文重点阐述了羟氯喹和氯喹的纳米制剂研究进展及抗肿瘤作用机制,整理了纳米制剂存在的问题及解决思路,以期为该制剂后期的临床应用转化奠定基础。     

纳米微粒靶向治疗脑癌研究进展

抗肿瘤药物的发展已进入新时期,纳米技术、新型靶向制剂的研究日趋成熟。由纳米技术与现代药物学结合形成的载药纳米微粒是一种新型的药物输送体系。本文通过检索大量相关文献,对纳米粒和靶向制剂在脑癌中的应用进行分析总结。     

多西紫杉醇纳米制剂的研究进展

摘 要多西紫杉醇作为一种高效广谱的抗肿瘤药,临床上用于不同类型实体瘤的治疗,但是水溶性差限制了其制剂的开发。纳米载药系统在提高难溶性药物溶解度、靶向给药、减少药物不良反应等方面极具发展前景。因此,采用纳米载体传递多西紫杉醇的研究受到广泛关注。本文综述了近几年来多西紫杉醇纳米制剂的研究进展,包括脂质体、纳米粒、生物共轭物、聚合物胶束、纳米乳、纳米囊、树枝状聚合物等,以期为新型纳米制剂的开发和应用提供参考。     

眼表应用制剂进行人体药代动力学研究的意义与可行性

药代动力学研究在药品研发及评价过程中具有重要作用。本文对眼表应用制剂的药代动力学研究的意义及可行性进行了探讨。为国内该类药物的研发提供参考。     

抗肿瘤药物的制剂研究

提高抗肿瘤药的治疗效果有三种方法:一是临床采用联合用药,以改进给药方案;二是用制剂技术改变药物在体内的动力学和剂量-效应的相关性,提高药物的治疗指数;三是寻找新的抗肿瘤药。在新药寻找及制剂研究过程中,常常遇到药剂学问题,如稳定性、溶解性等。我们的观点是开发简单的给药系统来解决若干抗肿瘤药的制剂问题。本文讨论改善药物溶解度和稳定性的方法。Ⅰ.抗肿瘤药物存在的问题影响许多有希望的抗肿瘤药进一步开发的主要制剂问题,是其稳定性差,水溶性不良,膜通透性差。而这些因素是理想制剂的     

氟尿嘧啶植入剂的研究进展及其在腺癌中的临床应用

氟尿嘧啶植入剂是一种新型的植入用缓释氟尿嘧啶制剂,是国家食品药品监督管理局批准的第一个抗肿瘤控释植入剂。氟尿嘧啶植入剂的主要有效成分为5-氟尿嘧啶。氟尿嘧啶植入剂可提高局部药物浓度,延长有效药物浓度时间,降低全身毒副反用。本文综述了氟尿嘧啶植入剂的药代动力学、药理作用及在腺癌中的临床应用。     

没食子酸的药理作用及其药物代谢动力学研究进展

目的综述中药及其复方制剂中的药效分子没食子酸(gallic acid,GA)的药理和药物动力学等研究进展,为进一步研究GA提供参考。方法查阅国内外文献,总结、提炼和阐明GA的研究现状和前景。结果 GA是牡丹皮、山茱萸等中药及其复方制剂中重要的功效成分,具有明显抗肿瘤、抗炎、抗氧化、抑菌和心脑血管保护等药理作用。经灌胃及静脉给药后,GA在动物体内的药代动力学过程均符合二室模型,大鼠灌胃给药的绝对生物利用度为42.9%。结论 GA作为牡丹皮等中药及其复方制剂中有效的中药分子用于开发抗心脑血管疾病、抗菌消炎、抗肿瘤的药物具有良好的前景。     

Anthelmintics for drug repurposing: Opportunities and challenges

Drug repositioning is defined as a process to identify a new application for drugs. This approach is critical as it takes advantage of well-known pharmacokinetics, pharmacodynamics, and toxicity profiles of the drugs; thus, the chance of their future failure decreases, and the cost of their development and the required time for their approval are reduced. Anthelmintics, which are antiparasitic drugs, have recently demonstrated promising anticancer effects in vitro and in vivo. This literature review focuses on the potential of anthelmintics for repositioning in the treatment of cancers. It also discusses their pharmacokinetics and pharmacodynamics as antiparasitic drugs, proposed anticancer mechanisms, present development conditions, challenges in cancer therapy, and strategies to overcome these challenges.     

丹参制剂与心脑血管、抗癌化学药联合用药的药动学研究进展

查阅近十年相关文献,对丹参制剂与心脑血管、抗肿瘤化学药联合用药的药动学研究进行整理分析和归纳总结。结果显示,丹参制剂对一些心脑血管和抗癌化学药的大鼠体内药动学参数会产生显著影响,如显著提高降脂药阿伐他丁、匹伐他丁和瑞伐他丁的血药浓度;显著提高抗癌药甲氨蝶呤和阿霉素的血药浓度或延长体内消除;分析整理文献,建议丹参制剂与抗血小板聚集药联合用药要慎重。联合用药时应关注其安全性、适当调整剂量,今后需要进一步开展基于代谢酶和转运体介导的药动学机制研究。     

植物来源抗肿瘤药联合化疗方案的临床疗效评价

目的本文旨在回顾性调查分析肿瘤患者应用包含植物来源抗肿瘤药化疗方案的疗效,为临床合理应用植物来源抗肿瘤药提供参考依据。方法收集山东省立医院肿瘤化疗科2010年12月至2011年12月应用植物来源抗肿瘤药治疗的肿瘤患者256例,设计调查表,采集信息,进行统计分析。结果本次调查发现采用植物来源抗肿瘤药组成的化疗方案71个,化疗次数834次。应用后临床症状得到相应改善,肿瘤有不同程度缓解。结论植物来源抗肿瘤药组成的不同化疗方案,各方案中不同药物的作用机制、药代动力学均不同,作用互补,能发挥共同杀灭肿瘤细胞的作用。在肿瘤治疗过程中,应根据患者情况合理选用,提高化疗效果。     

Advances in oral delivery of anti-cancer prodrugs

ABSTRACT

Introduction: Most anticancer drugs have poor aqueous solubility and low permeability across the gastrointestinal tract. Furthermore, extensive efflux by P-glycoproteins (P-gp) in the small intestine also limits the efficient delivery of anticancer drugs via oral route.

Area covered: This review explores the prodrug strategy for oral delivery of anticancer drugs. Different categories of oral anticancer prodrugs along with recent clinical studies have been comprehensively reviewed here. Furthermore, novel anticancer prodrugs such as polymer-prodrugs and lipid-prodrugs have been discussed in detail. Finally, various nanocarrier-based approaches employed for oral delivery of anticancer prodrugs have also been discussed.

Expert opinion: Premature degradation of anticancer prodrugs in the gastrointestinal tract could lead to variable pharmacokinetics and undesired toxicity. Despite their increased aqueous solubility, the oral bioavailability of several anticancer prodrugs are limited by their poor permeability across the gastrointestinal tract. These limitations can be overcome by the use of functional excipients (polymers, lipids, amino acids/dipeptides), which are specifically absorbed via transporters and receptor-mediated endocytosis. Oral delivery of anticancer prodrugs using nanocarrier-based drug delivery system is a recent development; however it should be justified based on the comparative advantages of encapsulating prodrug in a nanocarrier versus the use of anticancer prodrug molecule itself.     

Monitoring pharmacokinetics of anticancer drugs: non-invasive investigation using magnetic resonance spectroscopy

Magnetic resonance spectroscopy (MRS) offers the unique advantage of detecting, identifying and quantifying chemicals deep within the living body in a totally non-invasive manner. In studies on pharmacology and toxicology of anticancer drugs, MRS and the closely related technique magnetic resonance imaging (MRI) have many uses. MRS in particular, despite its low sensitivity, offers unique insights into pharmacokinetics (the changing concentration of the drug at its site of action) which can be monitored, and metabolism (both activation and detoxification) can be detected in real time. This review considers some recent work on (19)F, (31)P, (1)H and (13)C MRS of anticancer drugs. Future possibilities for (13)C MRS and (1)H MRS studies of drugs and their metabolites are considered in detail.     

Effects of anticancer drugs on the metabolism of the anticancer drug 5,6-dimethylxanthenone-4-acetic (DMXAA) by human liver microsomes

AIMS: To investigate the effects of various anticancer drugs on the major metabolic pathways (glucuronidation and 6-methylhydroxylation) of DMXAA in human liver microsomes. METHODS: The effects of various anticancer drugs at 100 and 500 microM on the formation of DMXAA acyl glucuronide (DMXAA-G) and 6-hydroxymethyl-5-methylxanthenone-4-acetic acid (6-OH-MXAA) in human liver microsomes were determined by high performance liquid chromatography (h.p.l.c.). For those anticancer drugs showing significant inhibition of DMXAA metabolism, the inhibition constants (Ki) were determined. The resulting in vitro data were extrapolated to predict in vivo changes in DMXAA pharmacokinetics. RESULTS: Vinblastine, vincristine and amsacrine at 500 microM significantly (P < 0.05) inhibited DMXAA glucuronidation (Ki = 319, 350 and 230 microM, respectively), but not 6-methylhydroxylation in human liver microsomes. Daunorubicin and N-[2-(dimethylamino)-ethyl]acridine-4-carboxamide (DACA) at 100 and 500 microM showed significant (P < 0.05) inhibition of DMXAA 6-methylhydroxylation (Ki = 131 and 0.59 microM, respectively), but not glucuronidation. Other drugs such as 5-fluoroucacil, paclitaxel, tirapazamine and methotrexate exhibited little or negligible inhibition of the metabolism of DMXAA. Pre-incubation of microsomes with the anticancer drugs (100 and 500 microM) did not enhance their inhibitory effects on DMXAA metabolism. Prediction of DMXAA-drug interactions in vivo based on these in vitro data indicated that all the anticancer drugs investigated except DACA appear unlikely to alter the pharmacokinetics of DMXAA, whereas DACA may increase the plasma AUC of DMXAA by 6%. CONCLUSIONS: These results indicate that alteration of the pharmacokinetics of DMXAA appears unlikely when used in combination with other common anticancer drugs. However, this does not rule out the possibility of pharmacokinetic interactions with other drugs used concurrently with this combination of anticancer drugs.     

Development of nanoparticulate systems with action in breast and ovarian cancer: nanotheragnostics

Abstract

The use of nanoparticulate systems with action in breast and ovarian cancer has been highlighted in recent years as an alternative to increasing the therapeutic index of conventional anticancer drugs. Thus, nanoparticles have advantageous characteristics in the treatment of cancer. Several nanocarriers of drugs and nanoparticles are described in the literature. The pharmacokinetics of the drugs can be modified by the use of nanocarriers, which in turn facilitate the specific delivery of the drug to the tumour cell. Therefore, the present work is a review that examines some nanosystems with nanoparticles for action in the treatment of breast cancer and ovarian cancer.     

Pharmacogenomics in drug-metabolizing enzymes catalyzing anticancer drugs for personalized cancer chemotherapy

Cancer chemotherapy is characterized by a broad range of efficacy and toxicity among patients. Most anticancer drugs show wide interindividual variability in pharmacokinetics and have narrow therapeutic windows. Since drug metabolism is often an essential determinant of interindividual variability in pharmacokinetics, pharmacogenomic studies of drug-metabolizing enzymes are expected to rationalize cancer chemotherapy in terms of patient, treatment, and dosage selection. Candidate gene approaches to pharmacogenomics are based on existing knowledge in clinical pharmacology, used to select the target(s) to be analyzed. So far, the candidate gene approach has provided important clues for pharmacogenomic-based personalized chemotherapy with 6-mercaptopurine (6-MP), solely metabolized by thiopurine S-methyltransferase (TPMT), and irinotecan, mainly detoxified by UDP-glucuronosyltransferase 1A1 (UGT1A1). Reduced activity of TPMT caused by polymorphisms in the TPMT gene and decreased activity of UGT1A1 caused by UGT1A1*28 are related to severe toxic effects of 6-MP and irinotecan, respectively. In response to these findings, the Food and Drug Administration in the United States has supported clinical pharmacogenetic testing by revising the package inserts for these anticancer drugs. The genome wide approach to pharmacogenomics has gradually evolved with continued progress in genome sciences and technologies. This approach can disclose previously unknown relations of factors, as well as identify potential multigenetic associations. The genome wide approach can also identify genes underlying the phenotypic effects of anticancer drugs. This approach may play a complemental role to the candidate gene approach in the future of cancer pharmacogenomics. This review describes recent progress in pharmacogenomics in the field of cancer chemotherapy.     

抗癌药物脂质体制剂药代动力学的研究进展

目的对抗癌药物脂质体制剂的药代动力学研究成果进行综述。方法参阅、归纳、总结相关文献,根据作用机制的不同对抗癌药物进行分类,分别阐述这些药物脂质体制剂的药代动力学研究概况。结果与结论脂质体制剂具有靶向性、缓释性的特点,能提高血药浓度和药物的生物利用度,使药物的消除速率慢于游离药物。脂质体制剂能够改善抗癌药物的治疗效果,并能降低药物的毒副作用。     

Boosting the oral bioavailability of anticancer drugs through intentional drug–drug interactions

Oral anticancer drugs suffer from significant variability in pharmacokinetics and pharmacodynamics partially due to limited bioavailability. The limited bioavailability of anticancer drugs is due to both pharmaceutical limitations and physiological barriers. Pharmacokinetic boosting is a strategy to enhance the oral bioavailability of a therapeutic drug by inhibiting physiological barriers through an intentional drug–drug interaction (DDI). This type of strategy has proven effective across several therapeutic indications including anticancer treatment. Pharmacokinetic boosting could improve anticancer drugs lacking or with otherwise unacceptable oral formulations through logistic, economic, pharmacodynamic and pharmacokinetic benefits. Despite these benefits, pharmacokinetic boosting strategies could result in unintended DDIs and are only likely to benefit a limited number of targets. Highlighting this concern, pharmacokinetic boosting has mixed results depending on the boosted drug. While pharmacokinetic boosting did not significantly improve certain drugs, it has resulted in the commercial approval of boosted oral formulations for other drugs. Pharmacokinetic boosting to improve oral anticancer therapy is an expanding area of research that is likely to improve treatment options for cancer patients.