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Since the publication of the first edition of Drug-Drug Interactions in , our knowledge of the various human drug-metabolizing enzyme systems and drug transporters has continued to grow at a rapid pace. This continued growth in knowledge has been Chemical and Enzymatic Aspects TexTBook ediTion Drug MetabolisM blogger.com 2 5/11/07 PM. OTE/SPH OTE/SPH uetrecht IHUSUetrecht May 10, Char Count= Informa Healthcare USA, Inc. 52 Vanderbilt Avenue New York, NY C by Informa Healthcare USA, Inc. Informa Healthcare is an Informa business No claim to original U.S. metabolism necessitate on-going studies of its biotransformation. In the first chapter, the principles underlying drug absorption, distribution, metabolism and elimination are described, with drug metabolism highlighted within the context of these fundamental processes. Chapters 2 and 3 deal with the chemistry of drug biotransformation,File Size: 2MB
Drug metabolism chemical and enzymatic aspects pdf free download
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Start by pressing the button below! Home Add Document Sign In Register. Drug Metabolism: Chemical and Enzymatic Aspects: Textbook Edition Home Drug Metabolism: Chemical and Enzymatic Aspects: Textbook Edition.
Author: Jack P. Uetrecht William Trager. DOWNLOAD PDF. Informa Healthcare is an Informa business No claim to original U. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number International Standard Book Number This book contains information obtained from authentic and highly regarded sources.
Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, drug metabolism chemical and enzymatic aspects pdf free download, drug metabolism chemical and enzymatic aspects pdf free download the author and the publisher cannot assume responsibility for the validity of all materials or for the consequence of their use.
No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers For permission to photocopy or use material electronically from this work, please access www.
CCC Rosewood Drive, Danvers, MA CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data Uetrecht, Jack P.
compiled] Jack P. Uetrecht, William Trager. Includes bibliographical references and index. ISBN hb : alk. paper ISBN hb : alk. paper 1. Drugs — Metabolism — Textbooks. Trager, William, — II. com and the Informa Healthcare Web site at www. In order to understand these effects it is necessary to understand both the structural parameters that are a direct cause of these effects as well as the factors that control the concentration of the drug in the body, such as absorption, metabolism, and elimination.
To fully appreciate drug action requires at least minimal expertise in a variety of disciplines such as chemistry, biochemistry, kinetics and biology. While complicated and demanding in its breadth such knowledge is central to the knowledge base of advanced students of Pharmacy, Pharmacokinetics, Medicinal Chemistry, Pharmacology and Toxicology. However, texts that focus on covering these disciplines in rationalizing drug action are rare.
Therefore, when considering the effects of an agent, all of the metabolites that the body produces from the agent must also be taken into consideration.
To try and address the gap in multidisciplinary knowledge required, as the title suggests, the focus of this book is on the chemistry, enzymology and to a lesser extent the kinetics of drug metabolism.
As indicated above an understanding of this subject at a minimum requires a basic understanding of the chemistry involved. It is also important that these processes be placed into a biological context. Therefore, Chapter 2 entitled "Background for Nonchemists" and Chapter 3 entitled "Background for Chemists" attempt to explicitly confront these issues and provide the necessary background and context.
Since chemically reactive metabolites have major implications for toxicity and since understanding their generation and properties requires the spectrum of disciplines outlined above a chapter is devoted to reactive metabolites. Finally, the only way to master the subject is with practice.
Sample problems with answers are provided to facilitate this process. Jack P. iii 1. Background for Nonchemists. Background for Chemists. Oxidation Pathways and the Enzymes That Mediate Them. Reductive Pathways. Hydrolytic Pathways. Conjugation Pathways. Reactive Metabolites. In addition, many patients will have an adverse reaction to a drug.
There are many reasons for these interindividual differences in drug response, both pharmacokinetic and pharmacodynamic. In order to begin to understand these differences, it is essential to understand what happens to a drug in the body.
Most drugs are given orally and some drugs have variable and incomplete absorption. The major determinant of absorption is the physical properties of the drug. Once in the body, most drugs are converted to multiple metabolites. This process can begin in the intestine or liver before the drug even enters the blood stream. Metabolism is often required in order for the body to eliminate a drug. However, some drugs are prodrugs, i, drug metabolism chemical and enzymatic aspects pdf free download.
Examples include enalapril, which has better oral bioavailability than the active agent, enalaprilate, and is readily activated by hydrolysis, and codeine, which must be metabolized to morphine in order to be an effective analgesic Fig. Drug metabolism chemical and enzymatic aspects pdf free download are several such metabolic enzymes that have common genetic polymorphisms caused by differences in a single nucleotide that influences enzyme expression or protein structure.
Classically, this leads to a bi- or even trimodal distribution of enzyme activity in a population. In principle, this could be due to differences in intrinsic activity of the enzyme, but in most cases the genetic variant has very low levels of the enzyme, usually because of rapid protein degradation 3.
Such polymorphisms can result in an interindividual difference of more than fold in the blood levels of a drug that is metabolized by a polymorphic enzyme.
Examples of polymorphic metabolic enzymes are listed in Table 1. Other metabolic enzymes have more of a Gaussian distribution of enzyme activity in a population, i. enzyme is strongly influenced by environmental factors. A good example of such an enzyme is CYP3A4 whose activity also varies greatly from one individual to another. In a recent study, it was found that the CYP3A4 activity of microsomes from different human livers varied by more than a factor of and this correlated strongly with the level of CYP3A4 protein; however, no single factor was found to be responsible for this large variation 6.
Furthermore, some metabolic pathways, such as glucuronidation and amino acid conjugation, are deficient at birth thereby making newborns more sensitive to drugs that are cleared by the enzymes involved. In the case of glucuronidation and newborns, this is particularly important because glucuronidation is the primary mechanism for the elimination of bilirubin, the breakdown product of hemoglobin, and the increase in the levels of bilirubin leads to jaundice, drug metabolism chemical and enzymatic aspects pdf free download.
Another aspect of drug variability that impinges upon therapeutics is that TABLE 1. Although many drugs require metabolism in order for them to be cleared from the body, many adverse effects of drugs are mediated by metabolites. In particular, it appears that most idiosyncratic drug reactions are caused by chemically reactive metabolites of drugs, and interindividual differences in metabolism of a drug may contribute to the idiosyncratic nature of these adverse reactions. However, the mechanisms of idiosyncratic reactions are not really understood, and even though there is evidence that reactive metabolites are involved, genetic polymorphisms in drug metabolism chemical and enzymatic aspects pdf free download responsible for forming the reactive metabolite that appears to be responsible for a given idiosyncratic reaction do not appear to be the major factor leading to the idiosyncratic nature of these adverse reactions 7.
The goal of this book is to provide a basic understanding of how drugs are converted to metabolites and how these transformations can change the physical and pharmacological properties of the drug. In order to gain a basic understanding of drug metabolism, it is essential to have a basic understanding of chemistry. To make this material more accessible to nonchemists, in Chapter 2 we review the basic chemical principles required to fully appreciate the subsequent chapters.
It is also important to be able to mathematically describe the rates of metabolism and other processes that control the concentration of a drug and therefore a review of pharmacokinetics is provided in Chapter 3.
Drug metabolism is commonly divided into phase I oxidation, reduction, and hydrolysis and phase II conjugation ; this implies that phase I metabolism occurs before phase II metabolism. However, if a drug can undergo phase II metabolism, phase I metabolism may make a minor contribution to drug metabolism chemical and enzymatic aspects pdf free download clearance of a drug and we have chosen to organize the pathways according to their chemical nature, i.
As mentioned above, many adverse effects of drugs appear to be due to chemically reactive metabolites; therefore, the last chapter is a discussion of reactive metabolites. Although the emphasis is on drugs, the same principles apply to any xenobiotic agent. The major difference between drugs and other xenobiotics such as environmental toxins is the dose.
Spear BB, Heath-Chiozzi M, Huff J. Clinical application of pharmacogenetics. Trends Mol Med ;7 5 — Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med ; 21 — Weinshilboum R, Wang L.
Pharmacogenetics: Inherited variation in amino acid sequence and altered protein quantity, drug metabolism chemical and enzymatic aspects pdf free download. Clin Pharmacol Ther ; 75 4 — Evans WE, Johnson JA. Pharmacogenomics: The inherited basis for interindividual differences in drug response. Annu Rev Genomics Hum Genet ; — Pharmacogenomics: Bench to bedside. Nat Rev Drug Discov ; 3 9 — He P, Court MH, Greenblatt DJ, et al. Factors influencing midazolam hydroxylation activity in human liver microsomes.
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25/2/ · Monday, February 25, Free Download of Drug Metabolism Chemical and Enzymatic Aspects pdf Book (Textbook Edition). Edited By: Jack P. Uetrecht & William Trager. Free Download of Drug Metabolism Chemical and Enzymatic Aspects pdf Book (Textbook Edition).Author: Pharmatech 21/6/ · 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 through the recognition of the chemical Drug Metabolism: Chemical and Enzymatic Aspects explains, to teachers and students alike, how a drug is metabolized, the potential effects of the metabolites, extensive material to help understand drug metabolism within a biological context, and practical problems and answers. Categories
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