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Reactive Drug Metabolites
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Book Synopsis Reactive Drug Metabolites by : Amit S. Kalgutkar
Download or read book Reactive Drug Metabolites written by Amit S. Kalgutkar and published by John Wiley & Sons. This book was released on 2012-09-06 with total page 445 pages. Available in PDF, EPUB and Kindle. Book excerpt: Closing a gap in the scientifi c literature, this first comprehensive introduction to the topic is based on current best practice in one of the largest pharmaceutical companies worldwide. The first chapters trace the development of our understanding of drug metabolite toxicity, covering basic concepts and techniques in the process, while the second part details chemical toxicophores that are prone to reactive metabolite formation. This section also reviews the various drug-metabolizing enzymes that can participate in catalyzing reactive metabolite formation, including a discussion of the structure-toxicity relationships for drugs. Two chapters are dedicated to the currently hot topics of herbal constituents and IADRs. The next part covers current strategies and approaches to evaluate the reactive metabolite potential of new drug candidates, both by predictive and by bioanalytical methods. There then follows an in-depth analysis of the toxicological potential of the top 200 prescription drugs, illustrating the power and the limits of the toxicophore concept, backed by numerous case studies. Finally, a risk-benefi t approach to managing the toxicity risk of reactive metabolite-prone drugs is presented. Since the authors carefully develop the knowledge needed, from fundamental considerations to current industry standards, no degree in pharmacology is required to read this book, making it perfect for medicinal chemists without in-depth pharmacology training.
Book Synopsis Adverse Drug Reactions by : Jack Uetrecht
Download or read book Adverse Drug Reactions written by Jack Uetrecht and published by Springer Science & Business Media. This book was released on 2009-12-18 with total page 552 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book provides the current state of knowledge of basic mechanisms of adverse drug reactions (ADRs). The main focus is on idiosyncratic drug reactions because they are the most difficult to deal with. It starts with a general description of the major targets for ADRs followed by a description of what are presently believed to be mediators and biochemical pathways involved in idiosyncratic drug reactions. There is also a description of several examples of ADRs that serve to illustrate specific aspects of ADR mechanisms. Eventually the book shows that ultimately better methods are needed to predict which drug candidates are likely to cause ADRs and which patients are at increased risk. But at present research seems to be far from this goal.
Book Synopsis Drug Metabolism by : Jack P. Uetrecht
Download or read book Drug Metabolism written by Jack P. Uetrecht and published by CRC Press. This book was released on 2007-06-20 with total page 182 pages. Available in PDF, EPUB and Kindle. Book excerpt: In order to understand drug metabolism at its most fundamental level, pharmaceutical scientists must be able to analyze drug compound structure and predict possible metabolic pathways in order to avoid the risk of adverse reactions that lead to the withdrawal of a drug from the market. This title is a comprehensive guide for recognizing the chemica
Book Synopsis Metabolite Safety in Drug Development by : Suzanne L. Iverson
Download or read book Metabolite Safety in Drug Development written by Suzanne L. Iverson and published by John Wiley & Sons. This book was released on 2016-07-05 with total page 351 pages. Available in PDF, EPUB and Kindle. Book excerpt: A reference on drug metabolism and metabolite safety in the development phase, this book reviews the analytical techniques and experimental designs critical for metabolite studies. It features case studies of lessons learned and real world examples, along with regulatory perspectives from the US FDA and EMA. • Reviews the analytical techniques and experimental designs critical for metabolite studies • Covers methods including chirality, species differences, mass spectrometry, radiolabels, and in vitro / in vivo correlation • Discusses target pharmacology, in vitro systems aligned to toxicity tests, and drug-drug interactions • Includes perspectives from authors with firsthand involvement in industry and the study of drug metabolites, including viewpoints that have influenced regulatory guidelines
Book Synopsis Transporters and Drug-Metabolizing Enzymes in Drug Toxicity by : Albert P. Li
Download or read book Transporters and Drug-Metabolizing Enzymes in Drug Toxicity written by Albert P. Li and published by John Wiley & Sons. This book was released on 2021-07-27 with total page 530 pages. Available in PDF, EPUB and Kindle. Book excerpt: TRANSPORTERS AND DRUG-METABOLIZING ENZYMES IN DRUG TOXICITY Explore up-to-date coverage on the interaction between drug metabolism enzymes, transporters, and drug toxicity with this leading resources Transporters and Drug-Metabolizing Enzymes in Drug Toxicity delivers a comprehensive and updated review of the relationship between drug metabolism, transporters, and toxicity, providing insights into a major challenge in drug development – accurate assessment of human drug toxicity. Combining two disciplines frequently considered independently of one another, the book combines drug metabolism and toxicology with a focus on the role of biotransformation on drug toxicity and as a major factor for species and individual differences. Mechanism and species differences in drug metabolizing enzymes and transporters are discussed, as are the methods used to investigate the role of drug metabolizing enzymes and transporters in drug toxicity. Finally, the distinguished authors describe promising new experimental approaches to accurately assessing human drug toxicity via the consideration of human-specific drug metabolism in toxicity assays. In addition to topics as diverse as extended clearance models, experimental approaches for the estimation of DILI potential of drug candidates and roles of transporters in renal drug toxicity, readers will also enjoy the inclusion of such subjects as: A thorough overview of and introduction to drug metabolism and transporters and drug toxicity An exploration of drug metabolism enzymes and transporter activities as risk factors of marketed drugs associated with drug-induced fatalities A discussion of human-based in vitro experimental models for the evaluation of metabolism-dependent drug toxicity A treatment of mechanism-based experimental models for the evaluation of BSEP inhibition and DILI An examination of transporters and cochlea toxicity Perfect for scientists, students, and practitioners with interests in metabolism, toxicology, and drug development in the pharmaceutical industry, Transporters and Drug-Metabolizing Enzymes in Drug Toxicity will also earn a place in the libraries of medicinal chemists, pharmacologists, biochemists, toxicologists, and regulators in the pharmaceutical and health industries.
Book Synopsis Involvement of Reactive Metabolites in Idiosyncratic Drug Reactions by :
Download or read book Involvement of Reactive Metabolites in Idiosyncratic Drug Reactions written by and published by . This book was released on 2003 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: PhD.
Book Synopsis Drug Metabolism in Drug Design and Development by : Donglu Zhang
Download or read book Drug Metabolism in Drug Design and Development written by Donglu Zhang and published by John Wiley & Sons. This book was released on 2007-11-16 with total page 448 pages. Available in PDF, EPUB and Kindle. Book excerpt: The essentials of drug metabolism vital to developing new therapeutic entities Information on the metabolism and disposition of candidate drugs is a critical part of all aspects of the drug discovery and development process. Drug metabolism, as practiced in the pharmaceutical industry today, is a complex, multidisciplinary field that requires knowledge of sophisticated analytical technologies and expertise in mechanistic and kinetic enzymology, organic reaction mechanism, pharmacokinetic analysis, animal physiology, basic chemical toxicology, preclinical pharmacology, and molecular biology. With chapters contributed by experts in their specific areas, this reference covers: * Basic concepts of drug metabolism * The role of drug metabolism in the pharmaceutical industry * Analytical techniques in drug metabolism * Common experimental approaches and protocols Drug Metabolism in Drug Design and Development emphasizes practical considerations such as the data needed, the experiments and analytical methods typically employed, and the interpretation and application of data. Chapters highlight facts, common protocols, detailed experimental designs, applications, and limitations of techniques. This is a comprehensive, hands-on reference for drug metabolism researchers as well as other professionals involved in pre-clinical drug discovery and development.
Book Synopsis Drug-Induced Liver Toxicity by : Minjun Chen
Download or read book Drug-Induced Liver Toxicity written by Minjun Chen and published by Humana Press. This book was released on 2018-03-21 with total page 667 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book provides a comprehensive view of the methodologies used for the study of liver toxicity encountered throughout the whole life cycle of a drug, from drug discovery, to clinical trial, post-marketing, and even clinical practice. Organized into six sections, the first section introduces the mechanisms contributing to drug-induced liver toxicity. The second and third section explore in silico and in vitro approaches used to help mitigate hepatotoxicity liability at the early stages of drug development. The fourth section describes methodologies applied in regulatory processes, including preclinical studies, clinical trials, and post-marketing surveillance. The fifth section discusses clinical hepatotoxicity. Emerging technologies are examined in the final section. As a volume in the Methods in Pharmacology and Toxicology series, chapters include the kind of expert advice that will lead to optimal results. Authoritative and practical, Drug-Induced Liver Toxicity serves all those who aim to improve assessment and understanding of hepatotoxic potentials of new medications and marketed drugs. Chapter 30 is open access under a CC BY 4.0 license via link.springer.com.
Book Synopsis Pharmacokinetics and Metabolism in Drug Design by : Dennis A. Smith
Download or read book Pharmacokinetics and Metabolism in Drug Design written by Dennis A. Smith and published by John Wiley & Sons. This book was released on 2012-05-14 with total page 269 pages. Available in PDF, EPUB and Kindle. Book excerpt: In this new edition of a bestseller, all the contents have been brought upto-date by addressing current standards and best practices in the assessment and prediction of ADMET properties. Although the previous chapter layout has been retained, substantial revisions have been made, with new topics such as pro-drugs, active metabolites and transporters covered in detail in a manner useful to the Drug Discovery scientist. The authors discuss the parameters and processes important for the absorption, distribution and retention of drug compounds in the body, plus the potential problems created by their transformation into toxic byproducts. While aimed at all those dealing professionally with the development and application of pharmaceutical substances, the readily comprehensible style makes this book equally suitable for students of pharmacy and related subjects. Uniquely comprehensive, the book relates physicochemistry and chemical structure to pharmacokinetic properties and ultimately drug efficacy and safety.
Book Synopsis Drug Metabolism Handbook by : Ala F. Nassar
Download or read book Drug Metabolism Handbook written by Ala F. Nassar and published by John Wiley & Sons. This book was released on 2009-01-28 with total page 1059 pages. Available in PDF, EPUB and Kindle. Book excerpt: A valuable reference tool for professionals involved in the industry, Drug Metabolism in Pharmaceuticals covers new tools such as LC-MS and LC-MS-NMR along with experimental aspects of drug metabolism. This work fills a gap in the literature by covering the concepts and applications of pharmaceutical research, development, and assessment from the point of view of drug metabolism. By providing both a solid conceptual understanding of the drug metabolism system, and a well illustrated, detailed demonstration and explanation of cutting edge tools and techniques, this book serves as a valuable reference tool for bench scientists, medical students, and students of general health sciences.
Book Synopsis Involvement of Reactive Metabolites in Idiosyncratic Drug Reactions by : Mukundan Baskar Mannargudi
Download or read book Involvement of Reactive Metabolites in Idiosyncratic Drug Reactions written by Mukundan Baskar Mannargudi and published by . This book was released on 2009 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Idiosyncratic drug reactions (IDRs) represent a significant medical problem and pose a great challenge to drug development. Circumstantial evidence suggests that, in most cases, reactive metabolites of the drug are responsible. The major focus of this thesis is the identification of reactive metabolites and the synthesis of analogs required to test several hypotheses related to involvement of metabolism and covalent binding in the mechanisms of IDRs. D-penicillamine is known to cause idiosyncratic autoimmune reactions in humans. The goal of this project was to test whether D-penicillamine covalently binds to macrophages and triggers downstream events leading to autoimmunity. To test a part of this hypothesis, D-penicillamine conjugated to biotin was synthesized. In summary, reactive metabolites of minocycline were found that likely explain why minocycline has an IDR profile unique among the tetracyclines. In addition, analogs of nevirapine and D-penicillamine required for mechanistic studies of nevirapine and D-penicillamine-induced IDRs were synthesized. These studies provide additional support for the involvement of reactive metabolites in the mechanisms of IDRs. Nevirapine, an anti-HIV drug, is associated with idiosyncratic skin rashes in humans. The goal of this project was to investigate whether the 12-hydroxylation pathway is responsible for the skin rash. To test a part of this hypothesis, 12-trideuteronevirapine, 12-OH-NVP sulfate, and several other analogs of nevirapine were synthesized. Minocycline is unique among tetracyclines in causing a significant incidence of a lupus-like syndrome and autoimmune hepatitis. In this study, we demonstrated that minocycline is oxidized to reactive intermediates by myeloperoxidase/H 2O2/Cl-, HOCl, horseradish peroxidase/H 2O2, or hepatic microsomes. When trapped with N-acetylcysteine (NAC), two adducts with protonated molecular ions at m/z 619 were isolated and analyzed by NMR. One represents attack of the aromatic D ring by NAC meta to the N, N-dimethylamino group, implying that the reactive intermediate was a quinone iminium ion. The other adduct, which was not observed when minocycline was oxidized by hepatic microsomes, indicates that the NAC is attached at the junction of the B and C rings, suggesting that the HOCl added across the double bond of the B ring leading to a reactive molecule, and then NAC displaced the chloride ion.
Book Synopsis Mechanisms of Drug Toxicity by : H. Rašková
Download or read book Mechanisms of Drug Toxicity written by H. Rašková and published by Elsevier. This book was released on 2013-10-22 with total page 113 pages. Available in PDF, EPUB and Kindle. Book excerpt: Mechanisms of Drug Toxicity, Volume 4 presents the proceedings of the 3rd International Pharmacological Meeting held in Sao Paulo, Brazil in 1966. The book discusses the drug-induced pathobiotic effects; the mechanisms of adverse reactions; and enzyme induction in the mechanism of chronic toxicity. The text also describes the influence of inducing substances on the growth of liver and microsomal electron transport systems; the quantitative aspects of chronic toxicity; and the facts and fallacies in predicting drug effects in human.
Book Synopsis Drug Metabolism Handbook by : Ala F. Nassar
Download or read book Drug Metabolism Handbook written by Ala F. Nassar and published by John Wiley & Sons. This book was released on 2022-11-18 with total page 1325 pages. Available in PDF, EPUB and Kindle. Book excerpt: A comprehensive explanation of drug metabolism concepts and applications in drug development and cancer treatment In the newly revised second edition of Drug Metabolism Handbook: Concepts and Applications in Cancer Research, a distinguished team of researchers delivers an incisive and robust exploration of the drug metabolism system and a well-illustrated and detailed explanation of the latest tools and techniques used in the research, pharmacology, and medicine. The book discusses the creation of new molecular entities, drug development, troubleshooting, and other highly relevant concepts, guiding readers through new applications in pharmaceutical research, development, and assessment. The latest edition offers updated content on metabolism basics and the application of a variety of new techniques to cancer treatment, including mass spectrometry, imaging, metabolomics, and immunotherapy. It also offers in-depth case studies highlighting the role of metabolism in drug development. Readers will also benefit from: A thorough introduction to drug metabolism, including a historical perspective, factors affecting metabolism, and biotransformations in drug metabolism Comprehensive discussions of technologies for in vitro and in vivo studies, including mass spectrometry and accelerating metabolite identification with mass spectrometry In-depth explorations of drug interactions, including discussions of enzyme inhibition and the characterization of cytochrome P450 mechanism-based inhibition Fulsome treatments of drug toxicity, including the role of drug metabolism in toxicity, and allergic reactions to drugs Perfect for medicinal chemists, pharmaceutical scientists, and toxicologists, Drug Metabolism Handbook: Concepts and Applications in Cancer Research, Second Edition will also earn a place in the libraries of analytical chemists and drug discovery professionals.
Book Synopsis Investigating the Role of Reactive Metabolites and Parent Compound in Drug Induced Liver Injury by : Nicola Marie Tidbury
Download or read book Investigating the Role of Reactive Metabolites and Parent Compound in Drug Induced Liver Injury written by Nicola Marie Tidbury and published by . This book was released on 2012 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Adverse drug reactions (ADRs) are a major problem for drug companies and healthcare providers alike. Although ADRs can present anywhere in the body, the liver frequently effected, due to the relatively large concentrations of drugs it encounters. Drug induced liver injury (DILI) can occur through several different mechanisms. Bioactivation of drugs to reactive metabolites is believed to be a crucial step in the development of many cases of DILI. Nefazodone, an anti-depressant which was withdrawn due to hepatotoxicity, has been shown to be bioactivated to a reactive quinone-imine. The role of the mitochondria and their involvement in DILI is being increasingly recognised. The biguanides are known mitochondrial toxins, and phenformin and buformin were removed from the market due to unacceptably high incidents of lactic acidosis. The aims of this thesis were two-fold; to assess the bioactivation and irreversible binding of nefazodone and it safer analogue buspirone and to use the biguanides to assess mitochondrial toxicity in primary hepatocytes. In liver microsomes, both nefazodone and buspirone demonstrated NADPH-dependent irreversible binding, however, nefazodone irreversible binding was 9-fold that of buspirone. The metabolism of both nefazodone and buspirone was extensive and consisted mainly of hydroxylation and N-dealkylation reactions. In rat and human liver microsomes supplemented with GSH, nefazodone formed GSH conjugates with m/z 791 and m/z 807. This implied that the conjugates were formed from bioactivation of para-hydroxy nefazodone and dihydroxy-nefazodone. In rat liver microsomes, buspirone did not form any GSH conjugates. Further investigations of nefazodone and buspirone were carried out in freshly isolated rat hepatocytes. Metabolism of nefazodone and buspirone was investigated and revealed extensive metabolism of both compounds; however, GSH conjugates of neither compound were discovered. At 6 hours, both nefazodone and buspirone demonstrated significant irreversible binding (117.54±15.32 pmol equiv./mg protein and 84.43±30.93 pmol equiv./mg protein respectively) but only nefazodone demonstrated a significant decrease in cell viability (19.25±18.26 % control viability). Inhibition studies, using ABT, significantly reduced the irreversible binding of nefazodone (49.34±4.64 pmol equiv./mg protein) but did not decrease cytotoxicity. This indicated that in rat hepatocytes the parent compound may be responsible for toxicity. Mitochondrial toxicity was investigated using the model mitochondrial toxins the biguanides. Initially, studies in cultured primary rat hepatocytes demonstrated that phenformin was the most potent mitochondrial toxin and dissipated the mitochondrial membrane potential, as measured by TMRM, within 24 hours (1.028±0.39% control fluorescence). This was taken forward to investigate mitochondrial toxicity in primary rat hepatocytes. Investigations into phenformin in rat hepatocytes demonstrated a high turnover to glucuronide metabolites and the novel metabolites [O, OMe] phenformin glucuronide and [2O] phenformin glucuronide were identified. Inhibition studies of CYP450 2D were undertaken using quinine (100μM) and this demonstrated significant inhibition of phenformin up to 200μM (AUC 47.30±47.30 without quinine vs AUC 648.80±121.28 with quinine). Despite increased phenformin concentrations, inhibition of phenformin metabolism did not produce overt cytotoxicity, however, lactate concentrations correlated with increased phenformin concentration. The work presented here highlights the need for a greater understanding of the role of bioactivation and irreversible binding in hepatotoxicity. It also demonstrates that whilst irreversible binding can help inform decisions as to whether a compound progresses into clinical trials, it should be made in the context of other safety assessments. Investigations into phenformin mitochondrial toxicity, illustrates the need to assess drugs and systems fully, to establish model compounds to investigate mechanisms of ADRs. A greater understanding of in vitro systems and the tools utilised to assess them, will benefit drug discovery and development. Ultimately, understanding these in vitro tests and the model compounds used to assess them, will help bridge the gap to man.
Author :Siamak Cyrus Khojasteh Publisher :Springer Science & Business Media ISBN 13 :1441956298 Total Pages :222 pages Book Rating :4.4/5 (419 download)
Book Synopsis Drug Metabolism and Pharmacokinetics Quick Guide by : Siamak Cyrus Khojasteh
Download or read book Drug Metabolism and Pharmacokinetics Quick Guide written by Siamak Cyrus Khojasteh and published by Springer Science & Business Media. This book was released on 2011-04-07 with total page 222 pages. Available in PDF, EPUB and Kindle. Book excerpt: Drug Metabolism and Pharmacokinetics Quick Guide covers a number of aspects of drug assessment at drug discovery and development stages, topics such as pharmacokinetics, absorption, metabolism, enzyme kinetics, drug transporters, drug interactions, drug-like properties, assays and in silico calculations. It covers key concepts, with useful tables on physiological parameters (eg. blood flow to organs in x-species, expression and localization of enzymes and transporters), chemical structure, nomenclature, and moieties leading to bioactivation (with examples). Overall it includes a number of key topics useful at the drug discovery stage, which would serve as a quick reference with several examples from the literature to illustrate the concept.
Book Synopsis Handbook of Toxicologic Pathology by : Wanda M. Haschek
Download or read book Handbook of Toxicologic Pathology written by Wanda M. Haschek and published by San Diego : Academic Press. This book was released on 2002 with total page 1012 pages. Available in PDF, EPUB and Kindle. Book excerpt: In volume I, the book covers toxicologic pathology in its basic aspects, including its definition, the basic biochemical and morphologic mechanisms underlying the discipline, the basic practice of toxicologic pathology (including special techniques) and issues essential to the understanding of toxicologic pathology such as risk assessment, experimental design, and statistical analysis. Next, the book moves to specific issues affecting the "practice" toxicologic pathology, including issues such as knowledge management, regulatory affairs and writing pathology reports. Finally, Volume I closes with several chapters that deal with specific classes of environmental toxicants such as endocrine disruptors and heavy metals. Volume II addresses the toxicologic pathology in a thoroughly standardized systems manner, addressing the basic structure and function of a particular organ system, its response to toxic injury, mechanisms of injury and methods of evaluation of such injury.-
Book Synopsis Mass Spectrometry in Drug Metabolism and Pharmacokinetics by : Ragu Ramanathan
Download or read book Mass Spectrometry in Drug Metabolism and Pharmacokinetics written by Ragu Ramanathan and published by John Wiley & Sons. This book was released on 2011-09-20 with total page 326 pages. Available in PDF, EPUB and Kindle. Book excerpt: This timely reference discusses mass spectrometry in drug metabolism and pharmacokinetic studies. With contributions by professionals from the pharmaceutical industry, this book begins with a review of current mass spectrometry techniques and applications, followed by discussions of various methods for using MS in drug metabolism studies and pharmacokinetics. Highlighting the critical importance of ADME studies for understanding how a drug is absorbed, distributed, metabolized, and excreted by the body, the book s focuses on the use of LC/MS and MALDI-MS. This is a valuable reference for scientists in the pharmaceutical industry, medicine, academia, and even those working in homeland defense.
