The content has been concisely summarized to help understand various steps involved in the phase 1 and pase 2 metabolism processes of xenobiotics. Phase i reactions include oxidation, reduction, and hydrolysis that are catalyzed by several enzymes including cytochrome p450. Phase 1 andor phase 2 some drugs undergo either phase 1 or phase 2 metabolism, but most undergo phase 1 metabolism followed by phase 2 metabolism. Answer to what are the possible metabolism of phase 1 and phase 2 for the drug carbamazepine skip navigation. Convert parent compound into a more polar hydrophilic metabolite by adding or unmasking functional groups oh, sh, nh2, cooh, etc. Markey laboratory of neurotoxicology nimh, nih nov. Sep 22, 2017 metabolism is the protective biochemical process by which our bodies alter xenobiotics either enzymatically or nonenzymatically. Drug botanical dietary supplement interactions can include inhibition or induction of 1 p450 enzymes involved in drug metabolism, 2 udpglucuronosyl transferases, 3 other phase i and phase ii enzymes, and 4 drug transporters and drug efflux proteins. Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. Metabolites formed in phase 2 are unlikely to be pharmacologically active. The drug metabolism process occurring in organs other than the figure 1. Metabolism drug metabolism is the anabolic and catabolic breakdown of drugs by living organisms.
Phase 1 drug metabolism ghosal 1 and 2 flashcards quizlet. Often these reactions involve the introduction of polar functional groups such as oh to drug molecules to make them more hydrophilic. Most phase 2 reactions inactivate drugs or the active metabolites formed from phase 1 reactions. Table showing examples of anaesthetic drug metabolism by cytochrome p450 system phases of metabolism metabolism of drugs is usually divided into phase 1 and phase 2. Tylenol can be metabolized by phase or phase 2 metabolism however the phase 2 metabolism predominates at lower concentrations of the drug. Phase ii drug metabolism is a conjugation reaction. The term metabolism is commonly used probably because products of drug transformation are called metabolites. Cyp3 drug metabolism 1 subfamily, 4 genes, 2 pseudogenes. The product for the p1 metabolism pathway is napqi which is toxic to the liver.
Genetic polymorphisms, drug metabolism and drug concentrations. 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. Learn vocabulary, terms, and more with flashcards, games, and other study tools. What are the possible metabolism of phase 1 and phase 2 for the drug carbamazepine. Phase i reactions involve hydrolysis, reduction and oxidation, exposing or introducing a functional group oh, nh 2, sh or cooh to increase reactivity and slightly increase hydrophilicity. 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.
Introduction to phase i and ii metabolisms phase i. 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 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. Quantitatively, the liver and gastrointestinal tract are the most important organs of drug metabolism.
Page 1 drug metabolism page 2 drug metabolism metabolism biotransformation of compounds is essential for survival of the organism. As the drug concentration increases the p1 pathway cyp is used more. A drug may inhibit one isoenzyme while being itself a substrate of another isoenzyme e. Drug metabolism is basically a process that introduces hydrophilic functionailities onto the drug molecule to facilitate excretion.
Phase i metabolism of drug candidates can be simulated in the laboratory using nonenzyme catalysts. Metabolic organs the chemistry of drug metabolism needs an elaborate understanding it is a fascinatingand a complicatedprocess. As drug concentration increases, metabolism shifts from firstorder to zeroorder kinetics. Phase i and phase ii reactions of drug authorstream. Biotransformation is the chemical modification or modifications made by an organism on a chemical compound. Atotw 179 the role of the liver in drug metabolism 17052010 page 3 of 6.
Phases i and ii of the metabolism of a lipophilic xenobiotic. It is highly variable among drugs and depends on biological conditions. The phase 1 oxidation reactions are carried out by cyps, flavincontaining monooxygenases fmo, and epoxide hydrolases eh. Phase i biotransformations include oxidation, reduction, and hydrolysis reactions. Although phase i drug metabolism occurs in most tissues, the primary and first pass site of metabolism occurs during hepatic circulation. Types of phase 1 and phase 2 metabolism associated enzymes and cofactors learn with flashcards, games, and more for free. This is because only watersoluble substances undergo excretion, whereas lipid soluble substances. Drugs get metabolize through various types of metabplic reactions, in this video, there is explanation about these reactions with examples.
During the last 1015 years, cytochrome p450 cyp 2c8 has emerged as an important drug metabolizing 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. Some drugs just undergo one or the other but the majority will undergo phase 1 and then phase 2 sequentially. Excretion of active drug often by the kidneys, but may also be in bile, or exhaled. The metabolism of xenobiotics is often divided into three phases. Intestinal mucosa, kidney, lungs, skin and adrenals intestinal mucosa intestinal wall is rich in esterases and lipases enzymes.
The cyps and fmos are composed of superfamilies of enzymes. In this phase an existing functional group already presents in the drug molecule or created by phase i metabolism such as alcohol, phenol, amine is masked or inactivated by a process of. Modeling of phase 2 metabolism enzymes drug metabolism. Biotransformation an overview sciencedirect topics. Protein binding attachment of the drug to blood proteins is an important factor influencing drug distribution. This is called conjugation and the product is called a conjugate. Phase 2 metabolism involves reactions that chemically change the drug or phase 1 metabolites into compounds that are soluble enough to be excreted in urine. Liver hepatic metabolism continues to be the most important route of metabolism for foreign ingested chemicals xenobiotics and drugs. Convert parent compound into a more polar hydrophilic metabolite by adding or unmasking. Path of a drug after administration by any route, a drug will reach the blood stream as. Siteorgans of drug metabolism the major site of drug metabolism is the liver.
Introduction to phase i and ii metabolisms phase i metabolism. Limited data are available on the pharmacodynamics of drugs. Phase 2 conjugation of a drug can occur in the absence of phase 1 metabolism. Cyp2c8 substrate drugs include amodiaquine, cerivastatin, dasabuvir, enzalutamide, imatinib, loperamide, montelukast, paclitaxel, pioglitazone, repaglinide, and rosiglitazone, and the. Pandya 9 phases of metabolism phase 1 reaction non synthetic phase phase 2. Ppt drug metabolism powerpoint presentation free to download id. Pharmacokinetic interactions between drugs and botanical. When the drug molecule is oxidized, hydrolyzed, or covalently attached to a hydrophilic species, the whole molecule becomes more hydrophilic, and is excreted more easily. A free powerpoint ppt presentation displayed as a flash slide show on id. This document is highly rated by students and has been viewed 490 times.
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. As explained in great detail in other chapters see 5. Cyp2c8 is highly expressed in human liver and is known to metabolize more than 100 drugs. Addition of the sulfonate moiety to the molecule of a parent compound or most often to the molecule of its metabolite originating in the oxidative phase of drug metabolism leads to formation of a watersoluble compound which is then easily eliminated from the body. 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. The content is so presented to allow the reader to compare various processes simultaneously and can easily memorize and learn about the topic. Many drugs are bound to blood proteins such as serum albumin the main blood protein and are not available as active drugs. Phase i biotransformation reactions introduce or expose functional groups on the drug with the goal of increasing the polarity of the compound. The nats identified to date and involved in human drug metabolism include nat 1 and nat 2.
Ppt drug metabolism powerpoint presentation free to. As a fundamental element in precision medicine, pharmacogenomics, the study of responses of individuals to medication based on their genomic information, enables the evaluation of some specific genetic variants responsible for an individuals. Pdf on feb 1, 2005, p david josephy and others published phase i and phase ii drug metabolism. Phase ii reactions include glucuronidation, sulfation, acetylation, methylation.
Whereas phase 1 metabolism involves hydroxylation, oxidation, and reduction pathways, phase 2 metabolism involves primarily conjugation of the phase 1 metabolites with a variety of groups e. Natural product dietary supplements might inhibit or induce the enzymes responsible for. The hydroxylated product produced from phase 1 reactions can also be conjugated by conjugation enzymes to more hydrophilic products, easier to excrete. The metabolism phase is absent for the few drugs that are not transformed. The interindividual genetic variations in drug metabolizing enzymes and transporters influence the efficacy and toxicity of numerous drugs.
Drugs undergo either phase i metabolism or phase ii metabolism in addition, a drug can undergo both eg. Theprimary site of drug metabolism is the smooth endoplasmic reticulum of the liver cell. K arthik kumar, 09bu1r0010, mlr institute of pharmacy. Renal excretion mechanisms are low at birth, but mature over a few months. Little overlap in substrate specificities of the two isoforms appears to exist.
Phase 1 andor phase 2 some drugs undergo either phase 1 or phase 2 metabolism, but most undergo phase 1. Describe the mechanisms of drug clearance and metabolism. This is because of the presenceof largeamounts of many varieties of enzymes. Phase i and phase ii reactions of drug authorstream presentation. Role of cytochrome p450 2c8 in drug metabolism and. Overview definition consequences types phase iii in detail enzyme inductioninhibition first pass metabolism. Drug metabolism enzyme activity is typically reduced in the neonate, but rapidly develops over the first year of life. Metabolism is an essential pharmacokinetic process, which renders lipid soluble and nonpolar compounds to water soluble and polar compounds so that. For example, phase i metabolism converts acetonitrile to hoch 2 cn, which rapidly dissociates into formaldehyde and hydrogen cyanide. 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.
The first drug metabolising polymorphism was described over 40 years ago for acetylation. Simple hydrolysis in the stomach is normally an innocuous reaction, however there are exceptions. Drug metabolism pptpowerpoint presentation, medical. Drug metabolism is the phase of biochemical transformation of the drug. Although there are many types of enzymes capable of biotransformation, cyps are the most. Phase iii refers to transportermediated elimination of drug and or metabolites from body normally via liver, gut, kidney, or lung. Metabolism or biotransformation the conversion from one chemical form of a substance to another. Often, phases 1 and 2 pathways work together to help in the removal of the xenobiotic. Previous question next question get more help from chegg. In this case, if 500 mg is present in the body at time zero, after metabolism, 450 mg may be present at 1 hour and 400 mg at 2 hours illustrating a maximal clearance of 50 mgh and no specific halflife.
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. View the rest of my pharmacology videos in order be. Drug metabolism can be divided into the phase i reactions functionalisation and the phase ii reactions conjugation. The drug metabolism happening in the liver is termed as hepatic metabolism. Phase ii conjugation reactions subsequent reaction in which a covalent linkage is. Phase i reactions convert the parent drug into more polar metabolites through introduction or exposing oh, sh, or nh2 functional groups. Oct 26, 2014 2 outline introduction history phases of metabolism phase i metabolism cytochrome p family phase ii metabolism first pass metabolism ante drug microsomal enzyme induction role of metabolism in drug discovery dr swaroop hs copyighted 3. Drug metabolism principles and applications 100% online. Metabolism of active drug to an inactive substance typically by the liver, but other organs kidney, lungs also metabolise some substances. But phase i metabolism converts acetonitrile to hoch 2 cn, which rapidly dissociates into formaldehyde and hydrogen cyanide, both of which are toxic.
Technology phase i and phase ii reactions of drug metabolism. Phase 1 metabolism can involve reduction or hydrolysis of the drug, but the most common biochemical process that occurs is oxidation. In addition to the liver, every biological tissue of the body has the ability to metabolize drugs. Oxidation is the chemical reaction that occurs when apples turn brown when exposed to the oxygen in air. Jan 06, 2019 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. In part ii we will discuss the kinetics of drug metabolism and the relationship of kinetic data to the pharmacokinetics of a drug. Apr 02, 2020 drug metabolism pptpowerpoint presentation, medical notes edurev is made by best teachers of. What are the possible metabolism of phase 1 and ph. Outline the phase 1 studies conducted to characterize the clinical pharmacology of a drug. Difference between phase i and phase ii metabolism compare. Types of biotransformation phasei or functionalization or non synthetic.
Oxidation is catalysed by cytochrome p450 enzymes and results in the loss of electrons from the drug. Phases i and ii of the metabolism of a lipophilic drug. Metabolism is an essential pharmacokinetic process, which renders lipid soluble and nonpolar compounds to water soluble and polar compounds so that they are excreted by various processes. 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. Part 1 of the article covers the basics of drug metabolism. Hydroxylation of an nmethyl group leads to expulsion of a molecule of formaldehyde, while oxidation of the omethyl groups takes place to a lesser extent.
759 159 18 341 127 453 882 1547 487 1604 854 1323 252 1498 1440 1354 598 578 1199 185 991 1022 95 91 1300 1261 471 928 1274 242 976 664 537 1607 232 982 1451 1323 108 488 791 8 1144 840 687