During drug metabolism, the active, lipophillic chemicals are converted into derivatives that can be easily eliminated through the urine or bile. Role of metabolism in pediatric and elderly new born has low g. Drug metabolic process involves two phases, the occurrence of which may vary from compound to compound. 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. 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. As will become clear, some enzymes catalyze only a single type of reaction. The enzymes involved in metabolism are present in many tissues but generally are more concentrated in the liver. It is almost a decade since the second edition of the handbook of drug metabolism was published. Phase i reactions convert the parent drug into more polar metabolites through introduction or exposing oh, sh, or nh2 functional groups. These enzymes are found in high concentrations in the smooth endoplasmic reticulum of the liver. Products of conjugation reactions have increased molecular weight and tend to be less active than their substrates, unlike phase i reactions which often produce active metabolites.
The absorption, distribution, and excretion of drugs objectives after studying this chapter, the reader should be able to. These processes determine the fate of a drug in the body. 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. Virtually every possible chemical reaction that a compound can undergo can be catalyzed by the drug metabolizing enzyme systems. 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. In part ii we will discuss the kinetics of drug metabolism and the relationship of kinetic data to the pharmacokinetics of a drug. Metabolism describes the chemical reactions that change drugs into compounds which are easier to eliminate. 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. Drug metabolism download ebook pdf, epub, tuebl, mobi. Most drugs undergo one or more metabolic reactions. In vitro metabolism studies in human and animal tissue. In other words, the metabolites are pharmacologically inactive. Phase i biotransformations include oxidation, reduction, and hydrolysis reactions.
Genetic factors in drug metabolism american family physician. What drugs metabolism has phase 2 preceding phase 1. The reactions will be discussed in terms of reaction type and, with respect to oxidation, site of enzyme. 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. Often these reactions involve the introduction of polar functional groups such as oh to drug molecules to make them more hydrophilic.
Phase 2 drug metabolism enzymatic conjugation reaction in the intestine and liver. Drug metabolism involves the enzymatic conversion of therapeutically important chemical species to a new molecule inside the human body. However, as this list indicates, other outcomes of metabolism are possible. Drug metabolism is an immense area of study where drugs undergo a range of enzymemediated chemical reactions, such as oxidation. Prodrug biochemical or chemical processes drug inactive active the definition of a prodrug is controversial in some circles. Drugs get metabolize through various types of metabplic reactions, in this video, there is explanation about these reactions with examples. Jun 01, 2008 pharmacokinetics is the study of the rate and extent of drug absorption, distribution, metabolism, and excretion. 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. 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. Phase ii reactions involve conjugation by coupling the drug or its metabolites to another molecule, such as glucuronidation, acylation, sulfate, or glicine. Drug metabolism is often considered during drug design.
Drugdruggene interactions and adverse drug reactions. Phase i reactions include oxidation especially by the cytochrome p450 group of enzymes, also called mixedfunction oxidases, reduction, deamination, and hydrolysis. 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. What phase 1 reaction is mainly performed by the cytochrome p450 enzymes also called mixedfunction enzymes. Phase i reactions of drug metabolism involve oxidation, reduction, or hydrolysis of the parent drug, resulting in its conversion to a more polar molecule. 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. This chapter focuses on phase ii biotransformation reactions also called. In this article, we discuss the basics of drug metabolism, the. 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. Conjugation reactions phase ii biotransformations attach a hydrophilic moiety onto drugmetabolite.
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. There are three possible results of phase 1 metabolism. Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. 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. These reactions include hydrolysis, reduction, and oxidation. Phase i and phase ii reactions of drug authorstream. Developing effective new drugs requires a thorough understanding of how the drugs will act once they are administered to the patient. In most cases, drug metabolism results in inactivation and accelerated elimination of drugs from the body. Formally, biotransformation of xenobiotics as well as endogenous compounds is subdivided into phase i and phase ii reactions. Phase ii biotransformations attach a hydrophilic moiety onto drugmetabolite. Metabolic organs the chemistry of drug metabolism needs an elaborate understanding it is a fascinatingand a complicatedprocess.
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. Examples of phase i drug substrates are listed in table 41. 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. Phase i reactions include oxidation, reduction, and hydrolysis that are catalyzed by several enzymes including cytochrome p450. The human cyp3a family is clinically very important because it has been shown to catalyze the metabolism of an amazingly large. Introduction to phase i and ii metabolisms phase i metabolism. Mar 19, 20 contentsintroduction to metabolism 1 2 drug metabolism introduction 3 sites of drug metabolism4 methods for study of drug metabolism56 4. Introduction to phase i and ii metabolisms phase i. 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. 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. Drug and toxin metabolism is divided into phase i and phase ii reactions. Biotransformation is the chemical modification or modifications made by an organism on a chemical compound.
Click download or read online button to get drug metabolism book now. Introduction of magnetic and supermagnetic nanoparticles in new approach of targeting. 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. 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. This functional group can be acted upon by the phase ii or conjugative enzymes. The resulting product is too polar to recross membranes back into tissues and is readily excreted. Handbook of drug metabolism 3rd edition pdf free pdf epub.
The chemical reactions normally associated with phase i and phase ii drug metabolism are given in table 1. For instance, a drug containing a benzene group may undergo phase i reactions e. 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. Sites on drugs where conjugation reactions occur include carboxyl cooh, hydroxyl oh, amino nh 2, and sulfhydryl sh groups. Drugdruggene interactions and adverse drug reactions the.
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. The final product usually contains a chemical reactive functional group oh, nh2, sh, cooh. Metabolism or biotransformation it is the enzymatic conversion from one chemical form of a substance to another. 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 learnatyourownpace online course is designed to provide scientists and regulatory professionals with a basic understanding of drug metabolism and its. Handbook of drug metabolism 3rd edition pdf free pdf. Sarita sharma assistant professor of pharmacology mumbai 2. Chapters 2 and 3 deal with the chemistry of drug biotransformation. The first drug metabolising polymorphism was described over 40. 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. Pdf on feb 1, 2005, p david josephy and others published phase i and. Intestinal wall is rich in esterases and lipases enzymes. Intestinal mucosa, kidney, lungs, skin and adrenals intestinal mucosa. Genetic polymorphisms, drug metabolism and drug concentrations.
Path of a drug after administration by any route, a drug will reach the blood stream as schematically shown in f2. A large variety of enzymes and metabolic reactions are presented in sections 2 and 3. 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. Theprimary site of drug metabolism is the smooth endoplasmic reticulum of the. Phase i reactions are broadly grouped into three categories, oxidation, reduction, and hydrolysis. Hepatic metabolism continues to be the most important route of metabolism for foreign ingested chemicals xenobiotics and drugs.
Induction of drug metabolizing enzymes often leads to accelerated metabolism of multiple drugs, not just the inducing drug itself. Metabolism is what happens to a drug when it undergoes biotransformation through enzymatic processes in the body. Metabolism is considered one of the main reasons for. The first drug metabolising polymorphism was described over 40 years ago for acetylation. The products of these chemical reactions are called metabolites. This is likely to be mediated by increasing polypharmacy, which increases the. Atotw 179 the role of the liver in drug metabolism 17052010 page 3 of 6. The process may result in pharmacologically active, inactive, or toxic metabolite. Such phase i functionalization reactions exposes unmasks or introduces a functional group oh, nh sh. As most small molecule drugs are lipophilic in nature, drug metabolism converts these hydrophobic compounds into more water soluble compounds that can be excreted. The economic and health burden caused by adverse drug reactions has increased dramatically in the last few years. Drugs need to reach the sites of action to elicit their pharmacological effects after administration into the body. Scatinas research interests include identification of metabolites, metabolicpathways and enzymes responsible, in vitroin vivo extrapolation, and. Metabolism is an essential pharmacokinetic process, which converts lipid soluble and.
Introduction to metabolism sum total of all the enzyme catalyzed reactions that occur in an organism. Phase ii reactions are generally the second reaction to occur in the metabolism of a drug, and produce a product which has decreased pharmacological activity and perhaps decreased toxicity. 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. Phase i reactions nonsynthetic, usually convert the parent drug to a more polar metabolite by oxidation, reduction, hydrolysis reactions. The primary objective of drug metabolism is to facilitate a drug s excretion by increasing its water solubility hydrophilicity. Most phase 2 reactions inactivate drugs or the active metabolites formed from phase 1 reactions. Prodrugs are inactive drugs that undergo a chemical or biochemical conversion to the active drug. Explain the meaning of the terms absorption, distribution, metabolism, and excretion. 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. This biotransformation can be deterred by replacing the hydrogen at the paraposition and using fluorine as a. This site is like a library, use search box in the widget to get ebook that you want. This process generally leads to more water soluble product which can be excreted via the kidneys or through bile into feces. Homework 1 drug metabolism 20 university of washington.
Drug metabolism is normally divided into two phases, phase i or functionalisation reactions and phase ii or conjugative reactions. 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. Sep 22, 2017 metabolism is the protective biochemical process by which our bodies alter xenobiotics either enzymatically or nonenzymatically. Phase 1 drug metabolism functional conversion to polar metabolites in. These type of reactions most often abolish biological activity. Drug metabolism can be divided into the phase i reactions functionalisation and the phase ii reactions conjugation.