This quiz has been uploaded to scribd by medical student james lamberg. A read is counted each time someone views a publication summary such as the title, abstract, and list of authors, clicks on a figure, or views or downloads the fulltext. A free online edition of this book is available at. Most metabolic products are less pharmacologically active. Cyp3a4 is very common to the metabolism of many drugs. Phase i reactions include oxidation, reduction, and hydrolysis that are catalyzed by several enzymes including cytochrome p450.
This issue of biofiles features selected products from sigmaaldrich s drug metabolism platform. Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through. Metabolism is an essential pharmacokinetic process, which renders lipid soluble and nonpolar compounds to water soluble and. In other words, the metabolites are pharmacologically inactive. Many drugs undergo a number of these reactions main function of phase i metabolism is to prepare the compound for phase ii metabolism mixed function enzyme system found in microsomes of many cells esp liver, kidney, lung. The drug metabolism process occurring in organs other than the figure 1.
There are three possible results of phase 1 metabolism. Oct 23, 20 reduction, oxidation, hydrolysis, conjugation, glucuronidation, acetylation, sulfaction, mnemonics. Phase i biotransformations include oxidation, reduction, and hydrolysis reactions. I and phase ii reactions and may lead to limited oral bioavailability. Phase i reactions include oxidation especially by the cytochrome p450 group of enzymes, also called mixedfunction oxidases, reduction, deamination, and hydrolysis. Phase i reactions phase i reactions also termed nonsynthetic reactions may occur by oxidation, reduction, hydrolysis, cyclization, and decyclization addition of oxygen or removal of hydrogen, carried out by mixed function oxidases, often in the liver. Phase i metabolism of drug candidates can be simulated in the laboratory. Hence, drug metabolism is an important aspect of living systems. In addition to the liver, every biological tissue of the body has the ability to metabolize drugs.
These type of reactions most often abolish biological activity. Examples of phase i drug substrates are listed in table 41. The key difference between phase i and phase ii metabolism is that the phase i metabolism converts a parent drug to polar active metabolites while phase ii metabolism converts a parent drug to polar inactive metabolites metabolism drug metabolism is the anabolic and catabolic breakdown of drugs by living organisms. Role of drug metabolism in drug mediated organ damage. Protons so that ferric oxene can reform and release the drug from the cyp 4. Phase 2 metabolism involves conjugation that is, the attachment of an ionised group to the drug. Preclinical drug metabolism and pharmacokinetics studies play a key role. A free powerpoint ppt presentation displayed as a flash slide show on id. The letrozole phase 1 metabolite carbinol as a novel probe. 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. Medicinal chemistry understanding drug metabolism december 3rd, 2014 medicinal chemistry this page focusses onstructural changes that occur when drugs undergo biotransformation and its importance in drug design and medicinal chemistry. Phase ii metabolism removes most of the drug prior to phase i and involves ugt1a1 and 1a6, as well as sult1a1, 1a34, and possibly 1e1.
The metabolism phase is absent for the few drugs that are not transformed. 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. Drugs can be metabolized by oxidation, reduction, hydrolysis, hydration, conjugation, condensation, or isomerization. This is done by adding a functional group oh here on to the drug compound. Phase i biotransformation reactions introduce or expose functional groups on the drug with the goal of increasing the polarity of the compound. Part 1 of the article covers the basics of drug metabolism. Introduction to metabolism sum total of all the enzyme catalyzed reactions that occur in an organism. More generally, xenobiotic metabolism 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 or poison. Phase ii enzymes undoubtedly play an important role in the detoxification of various xenobiotics. Other oxidative enzymes in drug metabolism include flavin monooxygenase and monoamine oxidase.
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. These enzymes are found in high concentrations in the smooth endoplasmic reticulum of the liver. Phases of biotransformation phase 1 parent drug polar metabolites phase 2 endogenous substrates highly polar conjugates. Drug metabolism is normally divided into two phases, phase i or functionalisation reactions and phase ii or conjugative reactions.
Phase i reactions convert the parent drug into more polar metabolites through introduction or exposing oh, sh, or nh2 functional groups. Markey nimh, nih mass spectrometry data center, nist november 14, 20. This results in activation or inactivation of the parent drug. Metabolism occurs in two phases, phase i metabolism, and phase ii metabolism.
These pathways are a form of biotransformation present in. Path of a drug after administration by any route, a drug will reach the blood stream as. Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. 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. These reactions include hydrolysis, reduction, and oxidation. Pdf on feb 1, 2005, p david josephy and others published phase i and phase ii drug metabolism. 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. Metabolism or biotransformation the conversion from one chemical form of a substance to another. Cytochrome p450 enzymes are the most important class of enzymes in phase i metabolism. Identification of ugt isoforms was performed using a panel of recombinant human ugt enzymes. Cytochrome p450 isozyme system play important role in phase i.
In phase 2, the active drug is made inactive and transformed in such a way that it is now suitable. Phasei drug metabolism free download as powerpoint presentation. In part ii we will discuss the kinetics of drug metabolism and the relationship of kinetic data to the pharmacokinetics of a drug. 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. From an anatomical and functional perspective, the liver plays a critical role in the disposition of therapeutic agents administered by the oral route, serving as a portal to the tissues, and represents the major site of drug metabolism. Often these reactions involve the introduction of polar functional groups such as oh to drug molecules to make them more hydrophilic. Drug metabolism can be divided into the phase i reactions functionalisation and the phase ii reactions conjugation. We know that elimination of apap involves phase i, ii, and iii metabolism. Learn vocabulary, terms, and more with flashcards, games, and other study tools. Phasei drug metabolism drug metabolism cytochrome p450. The term metabolism is commonly used probably because products of drug transformation are called metabolites.
During reduction reactions, a chemical can enter futile cycling, in which it gains a freeradical electron. These metabolic processes usually occur in the hepatocyte cytoplasm. 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. 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. Evolution of drug metabolism as a science post wwii pioneers richard tecwyn williams great britain 1942, worked on the metabolism on tnt with regard to toxicity in munitions workers. Mar 19, 20 contentsintroduction to metabolism 1 2 drug metabolism introduction 3 sites of drug metabolism4 methods for study of drug metabolism56 4. Phase i metabolism is predominantly mediated by cyp2e1 and produces a reactive metabolite. Introduction to phase i and ii metabolisms phase i.
Metabolism is an essential pharmacokinetic process, which renders lipid soluble and nonpolar compounds to water soluble and polar compounds so that. Phase i reactions in microsomes are cata lyzed by a group of enzymes known. A free radical refers to any molecule that has an odd number of electrons. Reductive metabolism is carried out by various enzymes.
Phase ii of metabolism may or may not be preceded by phase i reactions. 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. During phase 1, the inactive drug is made active by a set of drug metabolising enzymes. It is convenient to divide drug metabolism into two phases i and ii. Phase i metabolism converts the drug into metabolite by formation of a new functional group or modifying it, while phase ii metabolism or reactions involve conjugation with indigenous substance. Pdf on feb 1, 2005, p david josephy and others published phase i and. The enzymes involved in metabolism are present in many tissues but generally are more concentrated in the liver. Difference between phase i and phase ii metabolism.
Characterization of phase i and phase ii hepatic drug metabolism. Phase i and phase ii reactions of drug authorstream. Drug metabolizing organs every tissue has some ability to metabolize the drug liver is the primary organ of drug metabolism hepatic. It is highly variable among drugs and depends on biological conditions. The metabolism of drugs and allied organic compounds williams, 1949. The correct answers can be found in link at the end of this post. Although phase i drug metabolism occurs in most tissues, the primary and first pass site of metabolism occurs during hepatic circulation. Intestinal wall is rich in esterases and lipases enzymes. 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 drug metabolite. Choose from 198 different sets of phase 1 metabolism toxicity flashcards on quizlet. Phases of drug metabolism phase 1 drug metabolism functional conversion to polar metabolites in preparation for conjugation mostly in endoplasmic reticulum of the liver oh, nh2, sh, cooh often results in inactive metabolite, although sometimes metabolite more active prepares drug for phase 2 metabolism. Phase ii reactions involve conjugation of the drug with endogenous charged compounds such glutathionine, glucuronide, and glycine. The drug metabolism happening in the liver is termed as hepatic metabolism.
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. Examples of phase i drug substrates are listed in table 4 1. Phase 1 metabolism involves chemical reactions such as oxidation most common, reduction and hydrolysis. Intestinal mucosa, kidney, lungs, skin and adrenals intestinal mucosa. Here, we also talk aboutdrug metabolism and the essential factors that underpin this central discipline in. Free radicals generated from the cleavage of covalent bonds e. Phase i reactions of drug metabolism involve oxidation, reduction, or hydrolysis of the parent drug, resulting in its conversion to a more polar molecule. Liver is the primary site where majority of drug metabolism occurs in two phases.
In vivo drug metabolismdrug interaction studies 1999. Phase i metabolism includes oxidation, reduction, hydrolysis, and hydration and isomerization plus rarer misc. Drug metabolizing enzymes and biotransformation reactions 1 nalia at penner, caoline r woodward and, chandra prakash a. Drug metabolism principles and applications 100% online. The resulting product is too polar to recross membranes back into tissues and is readily excreted. Drug metabolism is the phase of biochemical transformation of the drug. Regulation of gene expression, enzyme activities, and impact of genetic variation. 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. In vivo drug metabolism drug interaction studies 1999. Understanding the cyp system is essential for advanced practitioners aps, as the consequences of drug drug interactions can be profound. These groups can include glutathione, methyl or acetyl groups. Jul 01, 20 cytochrome p450 cyp is a hemeprotein that plays a key role in the metabolism of drugs and other xenobiotics estabrook, 2003. We elucidated the contribution of udpglucuronosyltransferase ugt isoforms on the glucuronidation of carbinol. Of the drugs metabolized by phase i cytochrome p450s, approximately 75% are metabolized by just two.
As explained in great detail in other chapters see 5. Learn phase 1 metabolism toxicity with free interactive flashcards. The major difference between the drugs is that one is significantly metabolized by two p450 enzymes while the other is metabolized by only one p450 enzyme. On the other hand, these conjugations also play an essential role in the toxicity. In the intestine for example, several drug metabolising enzymes are presumed to decrease the bioavailability of orally administered drugs or to activate environmental carcinogens. Research has brought to you two drugs for the treatment of a disease. Ppt drug metabolism powerpoint presentation free to. Phase ii biotransformations attach a hydrophilic moiety onto drugmetabolite. Product areas highlighted include our portfolio of reagents for drug transport, phase i metabolism, and drug conjugate analysis. Hepatic metabolism continues to be the most important route of metabolism for foreign ingested chemicals xenobiotics and drugs. Xenobiotic metabolism, which includes drug metabolism. Phase ii reactions involve conjugation by coupling the drug or its metabolites to another molecule, such as glucuronidation, acylation, sulfate, or glicine. In phase ii more lipophilic groups are conjugated to the.
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