Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. Typically, oxidation is the most common phase i reaction. In such cases, called firstorder elimination or kinetics, the metabolism rate of the drug is a constant fraction of the drug remaining in the body ie, the drug has a specific halflife. Drugs can be metabolized by oxidation, reduction, hydrolysis, hydration, conjugation, condensation, or isomerization. Apr 12, 2018 drug metabolism as a discipline plays an important role in drug discovery and development and the effects of drug metabolism on pharmacokinetics pk, pharmacodynamics pd, and safety should be carefully considered. The resulting product is too polar to recross membranes back into tissues and is readily excreted. The enzymes involved in metabolism are present in many tissues but generally are more concentrated in the liver. Phase i reactions are broadly grouped into three categories, oxidation, reduction, and hydrolysis. In part ii we will discuss the kinetics of drug metabolism and the relationship of kinetic data to the pharmacokinetics of a drug. More generally, xenobiotic metabolism from the greek xenos stranger and biotic related to living beings is the set of metabolic pathways that modify the chemical structure of xenobiotics, which are compounds foreign to an organisms normal biochemistry, such as any drug. Phase i biotransformations include oxidation, reduction, and hydrolysis reactions.
The reactions will be discussed in terms of reaction type and, with respect to oxidation, site of enzyme. Explain the meaning of the terms absorption, distribution, metabolism, and excretion. The involved chemical modifications incidentally decrease or increase a drug s pharmacological activity andor halflife, the most extreme example being the metabolic activation of inactive prodrugs into active drugs, e. Phase 1 metabolism involves chemical reactions such as oxidation most common, reduction and hydrolysis. Phase ii reactions involve conjugation by coupling the drug or its metabolites to another molecule, such as glucuronidation, acylation, sulfate, or glicine. Drug and toxin metabolism is divided into phase i and phase ii reactions. In this article, we discuss the basics of drug metabolism, the.
Aug 04, 2008 joann scatina, phd, has over twentyfour years of drug metabolism experience, and is currentlyvice president of the drug metabolism division, drug safety and metabolism, for wyethresearch. These type of reactions most often abolish biological activity. Atotw 179 the role of the liver in drug metabolism 17052010 page 3 of 6. Sep 22, 2017 metabolism is the protective biochemical process by which our bodies alter xenobiotics either enzymatically or nonenzymatically. Phase ii biotransformations attach a hydrophilic moiety onto drugmetabolite. Phase i and phase ii reactions of drug authorstream. Click download or read online button to get drug metabolism book now. Hepatic metabolism continues to be the most important route of metabolism for foreign ingested chemicals xenobiotics and drugs. Role of metabolism in pediatric and elderly new born has low g. The chemical reactions normally associated with phase i and phase ii drug metabolism are given in table 1. The terms in the table below are a collection of items from the lectures that you should be able to define and relate in a sentence or two to drug metabolism as set out in the notes.
Drug metabolic process involves two phases, the occurrence of which may vary from compound to compound. It provides an invaluable introduction to the core areas of pharmacology and examines recent progress and advances in this fast moving field and its. Metabolism is an essential pharmacokinetic process, which converts lipid soluble and. This process generally leads to more water soluble product which can be excreted via the kidneys or through bile into feces. Conjugation reactions phase ii biotransformations attach a hydrophilic moiety onto drugmetabolite. Introduction to phase i and ii metabolisms phase i metabolism. In most cases, drug metabolism results in inactivation and accelerated elimination of drugs from the body. What phase 1 reaction is mainly performed by the cytochrome p450 enzymes also called mixedfunction enzymes. These processes determine the fate of a drug in the body.
However, as this list indicates, other outcomes of metabolism are possible. Drug metabolism can be divided into the phase i reactions functionalisation and the phase ii reactions conjugation. Sites on drugs where conjugation reactions occur include carboxyl cooh, hydroxyl oh, amino nh 2, and sulfhydryl sh groups. Most phase 2 reactions inactivate drugs or the active metabolites formed from phase 1 reactions. Induction or inhibition can occur either with the administration of a perpetrator drug that alters the victim drug metabolism or transport, or with the presence of loss or gainoffunction lof.
Major location of drug metabolizing enzymes dysfunction can lead to impaired drug metabolismdecreased enzyme activity first pass metabolism effected may inc 24 x bioavailiability results in exaggerated pharmacological responses and adverse effects cardiac failure causes decreased blood flow to the liver. The primary objective of drug metabolism is to facilitate a drug s excretion by increasing its water solubility hydrophilicity. The first drug metabolising polymorphism was described over 40 years ago for acetylation. This site is like a library, use search box in the widget to get ebook that you want.
Prodrugs are inactive drugs that undergo a chemical or biochemical conversion to the active drug. Drugs need to reach the sites of action to elicit their pharmacological effects after administration into the body. Theprimary site of drug metabolism is the smooth endoplasmic reticulum of the. The enzymecatalyzed reactions of phase i metabolism bind oxygen, hydrogen, water, or amino acids to the lipophilic drug molecule to expose or introduce a hydroxyl oh, amino nh 2, sulfhydryl sh, or carboxyl cooh polar functional group, and thus, result in a modest increase in the parent drugs water solubility. Pdf on feb 1, 2005, p david josephy and others published phase i and. Drugs get metabolize through various types of metabplic reactions, in this video, there is explanation about these reactions with examples. This chapter focuses on phase ii biotransformation reactions also called. Intestinal wall is rich in esterases and lipases enzymes. Induction of drug metabolizing enzymes often leads to accelerated metabolism of multiple drugs, not just the inducing drug itself. For example, rifampicin, an antibiotic used in tuberculosis, or phenytoin and phenobarbital, which are used as antiepileptic agents, all induce accelerated inactivation of each other and of contraceptive agents. Scatinas research interests include identification of metabolites, metabolicpathways and enzymes responsible, in vitroin vivo extrapolation, and. The absorption, distribution, and excretion of drugs objectives after studying this chapter, the reader should be able to.
Sarita sharma assistant professor of pharmacology mumbai 2. The products of these chemical reactions are called metabolites. Drugdruggene interactions and adverse drug reactions. Introduction to metabolism sum total of all the enzyme catalyzed reactions that occur in an organism. As most small molecule drugs are lipophilic in nature, drug metabolism converts these hydrophobic compounds into more water soluble compounds that can be excreted. What drugs metabolism has phase 2 preceding phase 1. Developing effective new drugs requires a thorough understanding of how the drugs will act once they are administered to the patient. This learnatyourownpace online course is designed to provide scientists and regulatory professionals with a basic understanding of drug metabolism and its. The economic and health burden caused by adverse drug reactions has increased dramatically in the last few years. Often these reactions involve the introduction of polar functional groups such as oh to drug molecules to make them more hydrophilic. Intestinal mucosa, kidney, lungs, skin and adrenals intestinal mucosa.
Reactions that increase water solubility by conjugation of the drug molecule with a polar moiety such as glucuronate, acetate, or sulfate cyp isozymes cytochrome p450 enzyme species eg, cyp2d and cyp3a4 that are responsible for much of drug metabolism. This is likely to be mediated by increasing polypharmacy, which increases the. Genetic factors in drug metabolism american family physician. Since its inception, the goal of the handbook was to provide a comprehensive text to serve as a graduate course in drug metabolism, a useful reference for academic and industrial drug metabolism scientists, but also as an important reference tool for those pursuing a career in drug discovery and. 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. As will become clear, some enzymes catalyze only a single type of reaction. Biotransformation is the chemical modification or modifications made by an organism on a chemical compound. Handbook of drug metabolism 3rd edition pdf free pdf. Path of a drug after administration by any route, a drug will reach the blood stream as schematically shown in f2. It is important that these pathways are studied as the route of metabolism of a drug can determine whether it shows any pharmacological or toxicological activity. This section takes a look at drug metabolism specifically, it provides a short overview of the various common conjugation reactions involved in the metabolism of drugs. It is almost a decade since the second edition of the handbook of drug metabolism was published. Phase 1 drug metabolism functional conversion to polar metabolites in. Feb 27, 2019 drug metabolism is the term used to describe the biotransformation of pharmaceutical substances in the body so that they can be eliminated more easily.
Provides a timely update to a key textbook on human drug metabolism the third edition of this comprehensive book covers basic concepts of teaching drug metabolism, starting from extreme clinical consequences to systems and mechanisms and toxicity. Phase i reactions include oxidation, reduction, and hydrolysis that are catalyzed by several enzymes including cytochrome p450. Phase 2 drug metabolism enzymatic conjugation reaction in the intestine and liver. Drug metabolism is an immense area of study where drugs undergo a range of enzymemediated chemical reactions, such as oxidation. Most drugs undergo one or more metabolic reactions. Drug metabolism involves the enzymatic conversion of therapeutically important chemical species to a new molecule inside the human body. Mar 19, 20 contentsintroduction to metabolism 1 2 drug metabolism introduction 3 sites of drug metabolism4 methods for study of drug metabolism56 4. Homework 1 drug metabolism 20 university of washington.
During drug metabolism, the active, lipophillic chemicals are converted into derivatives that can be easily eliminated through the urine or bile. Sult1 and 2 are most important in the metabolism of drugs found in liver, kidney, intestine, in cytosol catalyze the sulfation of alcohols roh phenols main group of substrates, aroh arylamines arnh 2 nhydroxy compounds rnhoh cofactor 3phosphoadenosine5phosphosulfate, paps is in limited supply, drug can overwhelm the system. Drug metabolism is conventionally described as consisting of phase 1 oxidation reactions, primarily mediated by cytochrome p450 enzymes in the liver, and phase 2 conjugations such as glucuronidation, sulphation and acetylation. For example, if 500 mg is present in the body at time zero, after metabolism, 250 mg may be present at 1 hour and 125 mg at 2 hours illustrating a half. Prodrug biochemical or chemical processes drug inactive active the definition of a prodrug is controversial in some circles. Examples of phase i drug substrates are listed in table 41. The process may result in pharmacologically active, inactive, or toxic metabolite.
The reactions are catalysed by enzymes and happen mostly in the liver, though some changes take place in the gut wall, lungs and blood plasma. The usual classification of drug metabolism enzymes and reactions as phase i or ii is somewhat misleading, as these reactions affect some drugs in a reverse order phase ii followed by phase i, e. In other words, the metabolites are pharmacologically inactive. Such phase i functionalization reactions exposes unmasks or introduces a functional group oh, nh sh. Phase i reactions of drug metabolism involve oxidation, reduction, or hydrolysis of the parent drug, resulting in its conversion to a more polar molecule. Metabolism is considered one of the main reasons for. Phase i reactions nonsynthetic, usually convert the parent drug to a more polar metabolite by oxidation, reduction, hydrolysis reactions. There are three possible results of phase 1 metabolism. Phase i reactions convert the parent drug into more polar metabolites through introduction or exposing oh, sh, or nh2 functional groups. The human cyp3a family is clinically very important because it has been shown to catalyze the metabolism of an amazingly large.
Genetic polymorphisms, drug metabolism and drug concentrations. Drugdruggene interactions and adverse drug reactions the. Metabolism describes the chemical reactions that change drugs into compounds which are easier to eliminate. Metabolic organs the chemistry of drug metabolism needs an elaborate understanding it is a fascinatingand a complicatedprocess. These reactions include hydrolysis, reduction, and oxidation.
In cases where oxidative metabolism by cyp enzymes is likely to be an important mechanism of drug clearance in humans, it is preferable to have contributions from multiple isoforms, as opposed to a single cyp again, to minimize the potential for drug drug interactions, whereas it is particularly. Joann scatina, phd, has over twentyfour years of drug metabolism experience, and is currentlyvice president of the drug metabolism division, drug safety and metabolism, for wyethresearch. Introduction to phase i and ii metabolisms phase i. In vitro metabolism studies in human and animal tissue. This functional group can be acted upon by the phase ii or conjugative enzymes. The remaining cyp isoforms involved in human drug metabolism are present in the liver in varying amounts, and each is thought to contribute 23% or less of the cypmediated drug oxidation reactions. The enzymecatalyzed reactions of phase i metabolism bind oxygen, hydrogen, water, or amino acids to the lipophilic drug molecule to expose or introduce a hydroxyl oh, amino nh 2, sulfhydryl sh, or carboxyl cooh polar functional group, and thus, result in a modest increase in the parent drug s water solubility. Introduction of magnetic and supermagnetic nanoparticles in new approach of targeting. Formally, biotransformation of xenobiotics as well as endogenous compounds is subdivided into phase i and phase ii reactions. A large variety of enzymes and metabolic reactions are presented in sections 2 and 3. The final product usually contains a chemical reactive functional group oh, nh2, sh, cooh. Chapters 2 and 3 deal with the chemistry of drug biotransformation.
Jun 01, 2008 pharmacokinetics is the study of the rate and extent of drug absorption, distribution, metabolism, and excretion. Drug metabolism is often considered during drug design. Handbook of drug metabolism 3rd edition pdf free pdf epub. Phase i reactions include oxidation especially by the cytochrome p450 group of enzymes, also called mixedfunction oxidases, reduction, deamination, and hydrolysis. Metabolism is what happens to a drug when it undergoes biotransformation through enzymatic processes in the body. Drug metabolism download ebook pdf, epub, tuebl, mobi. Virtually every possible chemical reaction that a compound can undergo can be catalyzed by the drug metabolizing enzyme systems. This biotransformation can be deterred by replacing the hydrogen at the paraposition and using fluorine as a. These enzymes are found in high concentrations in the smooth endoplasmic reticulum of the liver.
Drug metabolism is normally divided into two phases, phase i or functionalisation reactions and phase ii or conjugative reactions. The first drug metabolising polymorphism was described over 40. Reactions that convert the parent drug to a more polar watersoluble or more reactive product by unmasking or inserting a polar functional group such as oh, sh, or nh 2 phase ii reactions reactions that increase water solubility by conjugation of the drug molecule with a polar moiety such as glucuronate, acetate, or sulfate. Drug metabolism is an immense area of study where drugs undergo a range of enzymemediated chemical reactions, such as oxidation, reduction, hydrolysis, hydration, conjugation, and migration.
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