PEG-蛋白质类药物的体内代谢与安全性评价

聚乙二醇化蛋白质（pegylated protein,PEG-蛋白质）是延长蛋白质类药物半衰期的最有效的途径之一,通过延缓蛋白的排泄,提高其抗酶解的能力,增加其溶解性与稳定性,以及降低其免疫原性,可显著延长蛋白质类药物体内的生物活性,从而改善蛋白质类药物的药代动力学和药效学性质。由于方法学上的限制,PEG-蛋白质类药物的代谢、组织分布和排泄研究极具挑战,但众多的文献资料表明,聚乙二醇（polyethyleneglycol,PEG）分子的体内代谢与安全性已经确立,无需过度担心PEG-蛋白质类药物的安全性。将从PEG-蛋白质体内组织分布与排泄研究方法、PEG的代谢与安全性和PEG-蛋白质类药物动物和临床应用的安全性3方面介绍和评述PEG-蛋白药物的体内代谢与安全性评价问题。     

1999年～2001年我院钙离子通道阻滞剂类药物应用分析

目的 :了解钙离子通道阻滞剂类药物应用现状和发展趋势。方法 :对1999年～2001年我院钙离子通道阻滞剂类药物消耗品种和金额进行归类统计 ,并结合文献对其应用前景进行分析。结果 :该类药物的应用呈现平稳态势 ;二氢吡啶类药物应用最多 ;临床应用以国产和合资生产品种为主。结论 :钙离子通道阻滞剂类药物临床应用趋向控/缓释制剂     

1999年～2001年我院钙离子通道阻滞剂类药物应用分析

目的 :了解钙离子通道阻滞剂类药物应用现状和发展趋势。方法 :对1999年～2001年我院钙离子通道阻滞剂类药物消耗品种和金额进行归类统计 ,并结合文献对其应用前景进行分析。结果 :该类药物的应用呈现平稳态势 ;二氢吡啶类药物应用最多 ;临床应用以国产和合资生产品种为主。结论 :钙离子通道阻滞剂类药物临床应用趋向控/缓释制剂。     

硫酸基转移酶代谢功能相关的研究进展

随着药物研究领域对药物代谢酶的密切关注,它们对药物以及内源性化合物的代谢功能越来越被人们熟知.其中Ⅱ相代谢酶(如葡萄糖醛酸转移酶、硫酸基转移酶或谷胱甘肽-S-转移酶等)主要负责催化药物或者Ⅰ相代谢产物与底物进行结合,使其易于从人体排泄从而降低毒性反应.通过查阅国内外相关文献综述了近年来硫酸基转移酶代谢相关的研究进展,期望增强人们对药物代谢过程的认识,对医院临床合理用药提供一定的借鉴和指导.     

北京复兴医院钙离子阻滞剂应用分析

目的：调查首都医科大学附属复兴医院钙离子阻滞剂药物应用现状和发展趋势,为临床提供参考.方法：对2002年7月-2005年6月钙离子阻滞剂药物消耗品种和金额进行归类统计,并结合文献对其应用前景进行分析.结果：该类药物的应用3年来呈平稳态势,以二氢吡啶类药物应用最多,临床应用以国产和合资生产品种为主.结论：钙离子阻滞剂药物临床应用趋向于缓释和控释制剂.     

促黄体释放激素类似物(LHRH-A)在大鼠体内的分布、排泄及生物转化

在测定促黄体释放激素类似物(LHRH-A)的药物代谢动力学参数及血浆蛋白结合率的基础上。本文进一步测定了该药在大鼠体内各组织分布和药物排泄,并对它的体内代谢和生物转化进行初步研究。结果显示给药后在肾脏放射活性最高,其次是肝脏。在腺体组织也有较高放射性。该药主要从尿液中排出,尿液HPLC及血浆TLC分析结果表明尿液中无原形LHRH-A,只有其分解代谢产物。静脉给药后12′,血浆中LHRH-A的主要形式从游离型转为血浆蛋白结合型。     

丹酚酸B的药动学研究进展

丹酚酸B是目前研究较多的丹参酚酸成分之一,其口服吸收迅速,生物利用度低;分布取决于药物的理化性质、蛋白结合率及组织器官的特性;代谢具有非线性药动学特征,P450酶参与了此过程;排泄主要途径是胆汁。文中通过综述国内外有关丹酚酸B药动学研究进展,对丹酚酸B血浆生物样品预处理,检测方法,吸收、分布、代谢、排泄以及与其他药物相互作用几个方面进行了归纳分析。     

喹诺酮类抗菌药的概况与展望

描述了喹诺酮类抗菌药的作用机制,特别说明了DNA促旋酶的发现与证实在喹药物发展史上的重要意义;总结了结构改造,尤其是C1－、C6－、C7－和C8－位不同取代基的组合对其抗菌活性、药物动力学和代谢性质的影响;对早期喹诺酮和新喹诺酮类药物的抗菌活性、抗菌谱及耐药性等微生物学性质进行了比较;简述了喹诺酮类药物的吸收、分布、代谢和排泄等药物动力学性质;在说明喹诺酮类药物在临床上主要适于治疗呼吸道、胃肠道、泌尿道、皮肤软组织及关节等感染性疾病的同时,指出某些新喹诺酮类药物在其它抗感染领域的应用;总结了喹诺酮类药物常见的不良反应,用药注意事项及药物配伍禁忌;归纳了喹诺酮类药物的发展前景,预测随着人们对其构效关系、作用机制、耐药机制、药物相互作用、细胞毒性及新筛选模型等方面研究的进一步深化,这类药物在对付细胞感染方面必定会大有潜力可挖,同时也不排除它们在其它领域有所作为的可能性。     

肾功能不全病人的药物剂量调整

肾功能不全病人的药物剂量调整宋钟娟，顾金林（上海市华东医院２０００４０）药物在体内要经过吸收、分布、代谢、排泄四个主要的动力学过程，影响药物清除的主要二大组织是肝脏和肾脏。许多药物以原形从肾脏排泄，甚至一些有活性或毒性的代谢产物也经肾脏排泄。当肾功能...     

他汀类药物化学结构和理化性质对其药效及药动学特性的影响

他汀类药物能安全有效地降低血浆低密度脂蛋白胆固醇(LDL-C),是治疗高胆固醇血症的首选药物.已上市的他汀类药物作用机制大致相同,但化学结构有差异,导致其水溶性、亲脂亲水性不同,进而影响在人体内的吸收、分布、代谢及排泄特征.本文综述了此类药物化学结构和理化性质对其药效及药动学特性的影响.所有他汀类药物均有首过效应,因而药物可在肝脏富集.已上市药物中,瑞舒伐他汀降低LDL-C的效果较好,阿托伐他汀、辛伐他汀及普伐他汀次之.     

转运体介导的食物-药物相互作用

食物与药物之间的相互作用普遍存在,且作用机制也多种多样。目前,研究较多的是单个食物或食物中的某些营养成分通过调节药物转运体或代谢酶的功能从而影响药物的体内过程。食物对药物体内过程的影响包括吸收、分布、代谢、排泄四个方面,并且主要是调节其中参与的药物转运体和代谢酶的功能。转运体介导的食物对药物体内吸收的影响主要是通过调节肠上皮摄取型和外排型的转运体,从而影响药物的吸收;对分布的影响主要是通过调节体内一些屏障中的转运体;对代谢的影响主要是同时调节药物代谢酶和转运体;对排泄的影响是通过调节肾脏和肝脏胆汁排泄的药物转运体,从而影响药物的清除率。因此,转运体介导的食物与药物相互作用直接影响药物治疗的效果。     

Transporters as a determinant of drug clearance and tissue distribution

Transporters play an important role in the processes of drug absorption, distribution and excretion. In this review, we have focused on the involvement of transporters in drug excretion in the liver and kidney. The rate of transporter-mediated uptake and efflux determines the rate of renal and hepatobiliary elimination. Transporters are thus important as a determinant of the clearance in the body. Even when drugs ultimately undergo metabolism, their elimination rate is sometimes determined by the uptake rate mediated by transporters. Transporters regulate the pharmacological and/or toxicological effect of drugs because they limit their distribution to tissues responsible for their effect and/or toxicity. For example, the liver-specific distribution of some statins via organic anion transporters helps them to produce their high pharmacological effect. On the other hand, as in the case of metformin taken up by organic cation transporter 1, drug distribution to the tissue(s) may enhance its toxicity. As transporter-mediated uptake is a determinant of the drug elimination rate, drug–drug interactions involving the process of transporter-mediated uptake can occur. In this review, we have introduced some examples and described their mechanisms.

More recently, some methods to analyze such transporter-mediated transport have been reported. The estimation of the contributions of transporters to the net clearance of a drug makes it possible to predict the net clearance from data involving drug transport in transporter-expressing cells. Double transfected cells, where both uptake and efflux transporters are expressed on the same polarized cells, are also helpful for the analysis of the rate of transporter-mediated transcellular transport.     

Pharmacokinetics of the M1-agonist talsaclidine in mouse, rat, rabbit and monkey, and extrapolation to man

1. Talsaclidine is an M1-agonist under development for the treatment of Alzheimer's disease. The aim of the study was to investigate the absorption, distribution, metabolism and excretion (ADME) of single intravenous and oral doses of [14C]-talsaclidine in mouse, rat, rabbit and monkey. Previous data in humans showed that the drug was mainly excreted into the urine as the unchanged parent drug. The hypothesis was tested if animal data of drugs, which are mainly excreted renally, could be extrapolated to human. 2. The apparent volume of distribution at steady-state (V(ss)) was comparable in all animal species (2-5 l x kg(-1)) indicating an extensive distribution of the drug into tissues. The plasma protein binding was low and comparable in all species including man (< or = 7%). Elimination in terms of clearance was rapid-to-moderate depending on the species. The total plasma clearance (Cl) decreased in the order: mouse (128 ml x min(-1) x kg(-1))> rat (73.9) > monkey (10.6). Urinary excretion is the dominant route of excretion (> or = 86%). 3. A good correlation was achieved with human and animal data in allometric scaling of CI and V(ss). This confirms the hypothesis that renal filtration is scalable over the species and, given a comparable protein binding, animal data is predictive for man.     

Pharmacokinetics of the M1-agonist talsaclidine in mouse,rat, rabbit and monkey,and extrapolation to man

1. Talsaclidine is an M1-agonist under development for the treatment of Alzheimer's disease. The aim of the study was to investigate the absorption, distribution, metabolism and excretion (ADME) of single intravenous and oral doses of [¹⁴C]-talsaclidine in mouse, rat, rabbit and monkey. Previous data in humans showed that the drug was mainly excreted into the urine as the unchanged parent drug. The hypothesis was tested if animal data of drugs, which are mainly excreted renally, could be extrapolated to human. 2. The apparent volume of distribution at steady-state (V_ss) was comparable in all animal species (2-5 l.kg^-1     

Tissue distribution and pharmacodynamics: a complicated relationship

With few exceptions, drugs exert their effects not within the plasma compartment, but in the defined target tissues. The process of drug distribution to the active site constitutes the "link-bridge" of the pharmacokinetic/pharmacodynamic (PK/PD) relationship. In spite of the importance of drug distribution as a key factor in determining pharmacologic response, research on drug distribution has historically received much less attention than that of absorption, metabolism, and excretion. The negligence of research on drug distribution is due mainly to the inaccessibility of the target tissues for obvious ethical reasons. In addition, lack of reliable experimental tools to assess the distribution process is also a major contributing factor. Because of this negligence, drug distribution has been referred to as "the forgotten relative in clinical pharmacokinetics." Although recent advances in molecular biology have led to the identification of many drug transporters, many of the processes of drug distribution are still not fully understood. The primary aim of this article is to provide new insight into the mechanisms of drug distribution, with an attempt to describe the relationship between the drug distribution and pharmacologic response. In addition, the factors that affect the processes of drug distribution will also be reviewed. Also, validity of some key assumptions that are used to relate the processes of tissue distribution with pharmacologic activity will be discussed.     

Opportunities and challenges of incretin-based hypoglycemic agents treating type 2 diabetes mellitus from the perspective of physiological disposition

The treatment of patients with diabetes mellitus, which is characterized by defective insulin secretion and/or the inability of tissues to respond to insulin, has been studied for decades. Many studies have focused on the use of incretin-based hypoglycemic agents in treating type 2 diabetes mellitus (T2DM). These drugs are classified as GLP-1 receptor agonists, which mimic the function of GLP-1, and DPP-4 inhibitors, which avoid GLP-1 degradation. Many incretin-based hypoglycemic agents have been approved and are widely used, and their physiological disposition and structural characteristics are crucial in the discovery of more effective drugs and provide guidance for clinical treatment of T2DM. Here, we summarize the functional mechanisms and other information of the drugs that are currently approved or under research for T2DM treatment. In addition, their physiological disposition, including metabolism, excretion, and potential drug–drug interactions, is thoroughly reviewed. We also discuss similarities and differences in metabolism and excretion between GLP-1 receptor agonists and DPP-4 inhibitors. This review may facilitate clinical decision making based on patients' physical conditions and the avoidance of drug–drug interactions. Moreover, the identification and development of novel drugs with appropriate physiological dispositions might be inspired.     

Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense

In tumor cell lines, multidrug resistance is often associated with an ATP-dependent decrease in cellular drug accumulation which is attributed to the overexpression of certain ATP-binding cassette (ABC) transporter proteins. ABC proteins that confer drug resistance include (but are not limited to) P-glycoprotein (gene symbol ABCB1), the multidrug resistance protein 1 (MRP1, gene symbol ABCC1), MRP2 (gene symbol ABCC2), and the breast cancer resistance protein (BCRP, gene symbol ABCG2). In addition to their role in drug resistance, there is substantial evidence that these efflux pumps have overlapping functions in tissue defense. Collectively, these proteins are capable of transporting a vast and chemically diverse array of toxicants including bulky lipophilic cationic, anionic, and neutrally charged drugs and toxins as well as conjugated organic anions that encompass dietary and environmental carcinogens, pesticides, metals, metalloids, and lipid peroxidation products. P-glycoprotein, MRP1, MRP2, and BCRP/ABCG2 are expressed in tissues important for absorption (e.g., lung and gut) and metabolism and elimination (liver and kidney). In addition, these transporters have an important role in maintaining the barrier function of sanctuary site tissues (e.g., blood-brain barrier, blood-cerebral spinal fluid barrier, blood-testis barrier and the maternal-fetal barrier or placenta). Thus, these ABC transporters are increasingly recognized for their ability to modulate the absorption, distribution, metabolism, excretion, and toxicity of xenobiotics. In this review, the role of these four ABC transporter proteins in protecting tissues from a variety of toxicants is discussed. Species variations in substrate specificity and tissue distribution of these transporters are also addressed since these properties have implications for in vivo models of toxicity used for drug discovery and development.     

The ATP-binding cassette transporters and their implication in drug disposition: a special look at the heart

The passage of drugs across cell membranes dictates their absorption, distribution, metabolism, and excretion. This process is determined by several factors including the molecular weight of the compounds, their shape, degree of ionization, and binding to proteins. Accumulation of xenobiotics into tissues does not depend only on their ability to enter cells, but also on their ability to leave them. For instance, the role of efflux transporters such as ATP-binding cassette (ABC) proteins in the disposition of drugs is now well recognized. Actually, ABC transporters act in synergy with drug-metabolizing enzymes to protect the organism from toxic compounds. The most studied transporter from the ABC transporter superfamily, P-glycoprotein, was found to be overexpressed in tumor cells and associated with an acquired resistance to several anticancer drugs. P-glycoprotein, thought at first to be confined to tumor cells, was subsequently recognized to be expressed in normal tissues such as the liver, kidney, intestine, and heart. Even though information remains rather limited on the functional role of ABC transporters in the myocardium, it is hypothesized that they may modulate efficacy and toxicity of cardioactive agents. This review addresses recent progress on knowledge about the ABC transporters in drug disposition and more precisely their role in drug distribution to the heart.     

Effect of exercise on disposition and pharmacokinetics of drugs

The effect of various drugs on exercise in man and animal has been reported but there are very few reports which evaluate the effect of exercise on the disposition and pharmacokinetics of drugs. Exercise in general decreases the absorption after oral administration and increases absorption after intramuscular and subcutaneous administration. Exercise decreases the distribution and excretion of flow-limited drugs and increases the distribution and excretion for capacity-limited drugs. Treadmill or running wheel, but not swimming exercise diminishes or elevates the Phase I metabolism and glucuronidation. The effect of exercise on drug metabolism may be substrate specific, suggesting alterations in isozymes of Cyt P-450. Exercise also decreases glutathione concentration. Effect of exercise on drug disposition is also related to the other factors including temperature, pH, drug permeability, and barometric pressure; the most critical factor, however, appears to be altered blood flow which occurs with exercise. There is a wide inter- and intraindividual variation in the metabolism and pharmacokinetics of drugs due to exercise. It remains to be determined what factors play a major role in drug disposition as a consequence of exercise. Exercise influences the amount of drug reaching the receptor site, which has significant affect on pharmacodynamic activity. This aspect of pharmacology has great implications in therapeutics particularly for drugs which have a low margin of safety.     

Drug interactions with alcohol.

Ethanol and drugs can affect each other's absorption, distribution, metabolism, and excretion. When ingested together, ethanol can increase drug absorption by enhancing the gastric solubility of drugs and by increasing gastrointestinal blood flow. However, high concentrations of ethanol induce gastric irritation causing a pyloric spasm which in turn may delay drug absorption and/or reduce bioavailability. The 'quality' of the alcoholic beverage, independent of its ethanol content, can contribute to altered absorption of a drug. Ethanol is not bound to plasma proteins extensively enough to modify drug distribution. However, serum albumin levels in chronic alcoholics may be abnormally low so that some drugs, e.g. diazepam, have an increased volume of distribution. In addition to the amount ingested, the duration of regular intake determines the effect of ethanol on drug metabolism. Acute intake of ethanol inhibits the metabolism of many drugs but long term intake of ethanol at a high level (greater than 200g of pure ethanol per day) can induce liver enzymes to metabolise drugs more efficiently. At the present time there are no accurate means, with the possible exception of liver biopsy, to clinically predict the capacity of an alcoholic to metabolise drugs. Several drugs can inhibit the metabolism of ethanol at the level of alcohol dehydrogenase. Individual predisposition determines the severity of this drug-ethanol interaction. During its absorption phase, ethanol inhibits the secretion of antidiuretic hormone and is also able to induce increased excretion of a drug through the kidneys. However, chronic alcoholics with water retention may show reduced excretion of drugs via this route. At the pharmacodynamic level, ethanol can enhance the deleterious effects of sedatives, certain anxiolytics, sedative antidepressants and antipsychotics and anticholinergic agents, on performance. Mechanisms of lethal interactions between moderate overdoses of ethanol and anxiolytics/opiates/sedatives are poorly understood. On the other hand, certain peptides, 'nonspecific' stimulants, dopaminergic agents and opiate antagonists can antagonise alcohol-induced inebriation to a significant degree.