N Oxide Formation And Related Reactions In Drug Metabolism

The metabolic N-oxidation ofnitrogenousxenobiotics has been reported tc occur in many biologicalsystems, in addition to mammaliantissues, and the mechanisms appear to differ in many respects from those involved in oxidative attack atcarbon centres. Theextensive useofnitrogen-containing compounds as pharmaceuticals and chemical intermediates can lead to exposure to alarge numberofthese agentsunderwidelyvaryingconditions. Biotransformation of these xenobiotics by N-oxidative pathways can effect detoxication, butequallywellcaninduceformation ofcytotoxicmetabolites or potential promutagens and procarcinogens. The substantial progress, in recent years, in our understanding ofthe biochemistry and toxicology of N­ oxidation of nitrogenous structures has created a need for a synthesis of current knowledge. This book provides a wide-ranging review of the state-of-the-art in nitrogen xenobiochemistry divided into four parts. The introductory chapter discusses recent developments in trace analysis of radical intermediates and other N-oxygenated products by physical and immunochemical techniques. Special attention is given in Part Two to the enzymology of N-oxidation. Thus, detailed account is given of the mechanism and substrate specificity of the flavin-containing mono­ oxygenase and factors regulating its activity are addressed. A separate chapter outlines the polymorphic expression of flavoprotein-dependent reactions. Similarly, the mechanistic background and inducibility of cytochrome P-450-catalysed turnover of specific types of nitrogenous compounds is highlighted. Data are also compiled describing the role of peroxidative N-oxidation of xenobiotics in extrahepatic tissues lacking significant amounts ofcytochrome P-450.

In order to understand drug metabolism at its most fundamental level, pharmaceutical scientists must be able to analyze drug compound structures 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 comprehensive textbook will aid in guiding students throu

Consolidates the information LC-MS bioanalytical scientists need to analyze small molecules and macromolecules The field of bioanalysis has advanced rapidly, propelled by new approaches for developing bioanalytical methods, new liquid chromatographic (LC) techniques, and new mass spectrometric (MS) instruments. Moreover, there are a host of guidelines and regulations designed to ensure the quality of bioanalytical results. Presenting the best practices, experimental protocols, and the latest understanding of regulations, this book offers a comprehensive review of LC-MS bioanalysis of small molecules and macromolecules. It not only addresses the needs of bioanalytical scientists working on routine projects, but also explores advanced and emerging technologies such as high-resolution mass spectrometry and dried blood spot microsampling. Handbook of LC-MS Bioanalysis features contributions from an international team of leading bioanalytical scientists. Their contributions reflect a review of the latest findings, practices, and regulations as well as their own firsthand analytical laboratory experience. The book thoroughly examines: Fundamentals of LC-MS bioanalysis in drug discovery, drug development, and therapeutic drug monitoring The current understanding of regulations governing LC-MS bioanalysis Best practices and detailed technical instructions for LC-MS bioanalysis method development, validation, and stability assessment of analyte(s) of interest Experimental guidelines and protocols for quantitative LC-MS bioanalysis of challenging molecules, including pro-drugs, acyl glucuronides, N-oxides, reactive compounds, and photosensitive and autooxidative compounds With its focus on current bioanalytical practice, Handbook of LC-MS Bioanalysis enables bioanalytical scientists to develop and validate robust LC-MS assay methods, all in compliance with current regulations and standards.

Drug Metabolism: Current Concepts provides a comprehensive understanding of the processes that take place following ingestion of a medicinal agent or xenobiotic, with an emphasis on the crucial role of metabolism (biotransformation). How a sound knowledge of these phenomena is incorporated into the design of effective new drug candidates is also explained. The user-friendly text focuses on concepts rather than extraneous details and is supported by many illustrated examples of biotransformations as well as frequent references to current critical reviews and articles highlighting the nature of research objectives in this vibrant area of medicinal development. The final topic on strategies for drug design relies on the background provided by the rest of the book. This book is ideally suited as an advanced text for courses in drug metabolism for students of medicine, pharmacy, pharmacology, biochemistry; and for courses in drug design and drug delivery for students of medicinal chemistry. It is also appropriate for professional seminars or courses that relate to the fate of a drug in the body, drug interactions, adverse reactions and drug design.

Nicotine is an alkaloid which is present, together with a number of minor alkaloids, in tobacco and a wide variety of other plants. The introduction of tobacco as a therapeutic agent against diverse pathologi cal and physiological conditions resulted in the widespread exposure of people to nicotine, and the subsequent recognition of the pleasurable effects of tobacco consumption. Tobacco may be used for pleasure by smoking it in pipes, cigars or cigarettes or by taking it in unsmoked form as oral and nasal tobacco snuff. Nonsmokers are exposed to nico tine through plant material and side-stream tobacco smoke. This means that in humans nicotine is always utilized in the presence of a very large variety of natural compounds or their pyrolysis products, depend ing on the route of administration. These compounds may modify the absorption, distribution, metabolism and excretion of nicotine and hence alter the duration of its pharmacological action. In recent years the use of nicotine in chewing gum and cutaneous patches has been developed as an aid to smoking cessation. The toxic properties of nicotine make it useful as an insecticide, which has led to its use in agriculture and horticulture. It has also recently been recog nized that tobacco consumption may be beneficial in the prevention of Parkinson's disease or in alleviating inflammatory bowel syndrome. The above observations have continued to stimulate research into the mode of action of this relatively simple molecule.

A practice-oriented desktop reference for medical professionals, toxicologists and pharmaceutical researchers, this handbook provides systematic coverage of the metabolic pathways of all major classes of xenobiotics in the human body. The first part comprehensively reviews the main enzyme systems involved in biotransformation and how they are orchestrated in the body, while parts two to four cover the three main classes of xenobiotics: drugs, natural products, environmental pollutants. The part on drugs includes more than 300 substances from five major therapeutic groups (central nervous system, cardiovascular system, cancer, infection, and pain) as well as most drugs of abuse including nicotine, alcohol and "designer" drugs. Selected, well-documented case studies from the most important xenobiotics classes illustrate general principles of metabolism, making this equally useful for teaching courses on pharmacology, drug metabolism or molecular toxicology. Of particular interest, and unique to this volume is the inclusion of a wide range of additional xenobiotic compounds, including food supplements, herbal preparations, and agrochemicals.

This book provides a comprehensive, organized, and concise overview of xenobiotic metabolic enzymes and their health implications. The subjects addressed are broad in scope with an emphasis on recent advances in research on biochemical and biomedical aspects of these enzymes. The xenobiotics discussed include not just drugs, but also food, smoke, and other environmental chemicals. The subjects covered in this work include: metabolic enzymes and their catalyzed reactions, reactive intermediates generated from metabolic activation, oxidative stress mediated by electrophilic reactive intermediates, bioactivation - mediated cellular and functional damages, activation of Nrf2 – ARE pathway, genetic variations affecting metabolic enzyme expression, enzyme polymorphisms affecting xenobiotic - mediated toxicity, induction of metabolic enzymes for health benefits, and a diversity of metabolic enzyme modulators.