In the intestine for example, several drug metabolising enzymes are presumed to decrease the bioavailability of orally administered drugs or to activate environmental carcinogens. Phase i reactions of drug metabolism involve oxidation, reduction, or hydrolysis of the parent drug, resulting in its conversion to a more polar molecule. Phase i metabolism includes oxidation, reduction, hydrolysis, and hydration and isomerization plus rarer misc. Pdf on feb 1, 2005, p david josephy and others published phase i and phase ii drug metabolism. Overview definition consequences types phase iii in detail enzyme inductioninhibition first pass metabolism. Phase i and phase ii biotransformation reactions catalyzed by xenobiotic biotransforming enzymes are generally divided into two groups. Therefore, amcbal culturing makes the heparg cells more suitable for testing metabolism and toxicity of drugs. Phase 2 excretion toxicity x3oh x2oh x1oh cyp2d6 cyp2c9 cyp3a4 drug x p450 enzymes metabolites fe o n n n n 2 drug metabolism is a major determinant of drug clearance from the body and drug halflife in the blood. An important point to note is that some drugs dont undergo phase i metabolic reaction but instead are directly deactivated by phase ii reactions.
Phase ii reactions involve conjugation by coupling the drug or its metabolites to another molecule, such as glucuronidation, acylation, sulfate, or glicine. Phase i oxidative metabolism variably developed phase ii. Product areas highlighted include our portfolio of reagents for drug transport, phase i metabolism, and drug conjugate analysis. Simple hydrolysis in the stomach is normally an innocuous reaction, however there are exceptions.
This study was a phase 1, openlabel, singlecenter, singledose study conducted from august 2012 to september 2012. Technology phase i and phase ii reactions of drug metabolism. Induction of phase i, ii and iii drug metabolismtransport. Drug metabolism can be divided into the phase i reactions functionalisation and the phase ii reactions conjugation. Often these reactions involve the introduction of polar functional groups such as oh to drug molecules to make them more hydrophilic. Many drugs are bound to blood proteins such as serum albumin the main blood protein and are not available as active drugs. 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. Jan 06, 2019 the key difference between phase i and phase ii metabolism is that the phase i reactions convert a parent drug to polar active metabolites through unmasking or insertion of polar functional groups whilst phase ii reactions convert a parent drug to polar inactive metabolites through conjugation of subgroups to sh, oh and nh 2 functional. Introduction to phase i and ii metabolisms phase i metabolism.
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. Download as ppt, pdf, txt or read online from scribd. The resulting product is too polar to recross membranes back into tissues and is readily excreted. Conjugation reactions phase ii biotransformations attach a hydrophilic moiety onto drugmetabolite. Phase i and phase ii reactions of drug authorstream. Drug metabolizing enzymes and biotransformation reactions 1 nalia at penner, caoline r woodward and, chandra prakash a. 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. Drug metabolizing enzymes dmes play central roles in the metabolism, elimination and detoxification of xenobiotics and drugs introduced into the human body. Phase i reactions convert the parent drug into more polar metabolites through introduction or exposing oh, sh, or nh2 functional groups. Phasei drug metabolism drug metabolism cytochrome p450. 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. This issue of biofiles features selected products from sigmaaldrich s drug metabolism platform.
Occurs in the cytosolic fraction of the liver cells 4, 6. Biotransformation drug metabolism linkedin slideshare. Phase 1 and phase 2 drug metabolism and bile acid production. We know that elimination of apap involves phase i, ii, and iii metabolism. Protein binding attachment of the drug to blood proteins is an important factor influencing drug distribution. Prebiotics are nondigestible substrates found in foods such. Introduction to phase i and ii metabolisms phase i. Overview definition consequences types phase iii in detail. Quizlet flashcards, activities and games help you improve your grades. 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. Phase i metabolism is predominantly mediated by cyp2e1 and produces a reactive metabolite. It is highly variable among drugs and depends on biological conditions.
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. Phase i biotransformation reactions introduce or expose functional groups on the drug with the goal of increasing the polarity of the compound. 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. The drug metabolism process occurring in organs other than the figure 1. Phase ii reactions include glucuronidation, sulfation, acetylation, methylation, conjugation with glutathione, and conjugation with amino acids glycine, taurine and glutamic acid that strongly increase hydrophilicity. 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, phase i metabolism converts acetonitrile to hoch 2 cn, which rapidly dissociates into formaldehyde and hydrogen cyanide. Concluding, culturing heparg cells in the amcbal yields substantial phase 1 and phase 2 drug metabolism, while maintaining high viability, rendering dmso addition superfluous for the promotion of drug metabolism. This chapter focuses on phase ii biotransformation reactions also called. Homework 1 drug metabolism 20 university of washington.
Phase ii of metabolism may or may not be preceded by phase i reactions. Occurs in the smooth endoplasmic reticulum ser of the liver cells 2. Phase ii reactions involve conjugation of the drug with endogenous charged compounds such glutathionine, glucuronide, and glycine. Phase ii enzymes undoubtedly play an important role in the detoxification of various xenobiotics. Phase 1 aspirin 2ethanoyloxybenzoic acid hydrolyses to produce 2hydroxybenzoic acid and ethanoic acid. Conjugation reactions phase ii biotransformations attach a hydrophilic moiety onto drug metabolite. In addition to the liver, every biological tissue of the body has the ability to metabolize drugs. Induction of phase i, ii and iii drug metabolismtransport by. Phenyl sulphate, the final metabolite is very water soluble and is readily. Glutathione gsh or mercapturic acid conjugations 5.
Phase 1 and phase 2 drug metabolism and bile acid production of heparg cells in a bioartificial liver in absence of dimethyl sulfoxide ruurdtje hoekstra, geert a. 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. Phase 2 drug metabolism enzymatic conjugation reaction in the intestine and liver to form mostly inactive polar metabolite that is excreted in urine or feces mostly in the cellular cytosol except glucuronidation enzyme, which is a microsomal enzyme. Although phase i drug metabolism occurs in most tissues, the primary and first pass site of metabolism occurs during hepatic circulation. The study consisted of screening day 28 to day 2, baseline day 2 to day 1. 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. Xenobiotic metabolism enzymes occur in highest concentration in liver, also in lung, small intestine and other sites of entry. 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 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. Phase ii reactions include glucuronidation, sulfation, acetylation, methylation. Formally, biotransformation of xenobiotics as well as endogenous compounds is subdivided into phase i and phase ii reactions.
Reactions which introduce or unmask hydrophilic groups in the drug structure functionalisations. Genetic polymorphisms, drug metabolism and drug concentrations. Prebiotics and probiotics the next issue of biofiles will explore the functionality of prebiotics and probiotics. Contains hepatic drugmetabolising enzymes cytochrome p450 referred to as cyp 1, 2. Phase i metabolism absorption, distribution, metabolism and excretion adme. Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. The drug metabolism happening in the liver is termed as hepatic metabolism. The first drug metabolising polymorphism was described over 40 years ago for acetylation. Reactions that increase water solubility by conjugation of the drug molecule with a polar moiety such as glucuronate, acetate, or.
The involved chemical modifications incidentally decrease or increase a drugs pharmacological activity andor halflife, the most extreme example being the metabolic activation of inactive prodrugs into active drugs, e. Choose from 500 different sets of phase 2 metabolism drug flashcards on quizlet. In these reactions, the molecule oh o o ch 3 figure 2 warfarin is used as an antipharmacologically active and they are excreted by the kidney. Most of the tissues and organs in our body are well equipped with diverse and various dmes including phase i, phase ii metabolizing enzymes and phase iii transporters, which are present in abundance either at the basal unstimulated level. 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. 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. Learn phase 2 metabolism drug with free interactive flashcards. As drug concentration increases, metabolism shifts from firstorder to zeroorder kinetics. The conjugated metabolite has larger size and increased water solubility, which allows for secretion into the bile or urine. Most phase 2 reactions inactivate drugs or the active metabolites formed from phase 1 reactions.
The complications of drug drug interactions mainly depends on the induction or inhibition of metabolic enzymes drug metabolism can be divided into two distinct categories. Difference between phase i and phase ii metabolism compare. Phase i reactions include oxidation, reduction, and hydrolysis that are catalyzed by several enzymes including cytochrome p450. P450 drug metabolism i 20 university of washington. The enzymes of phase i metabolism, most notably the cytochrome p450 enzymes, only slightly increase water solubility of the drug molecule and does not always increase it enough to facilitate. However, benzene can also be oxidized by phase i metabolism to. 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. We rely on drug metabolism when we dose and would like to treat every individual the same way. 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. The primary objective of drug metabolism is to facilitate a drugs excretion by increasing its water solubility hydrophilicity. Drug metabolism is the phase of biochemical transformation of the drug. 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. Currently, data from in vivo preclinical and in vitro human tissue studies are used in predicting the safety and human pharmacokinetics, and assessing the potential of a new chemical entity nce as a successful.
K arthik kumar, 09bu1r0010, mlr institute of pharmacy. Atotw 179 the role of the liver in drug metabolism 17052010 page 3 of 6. Chapters 2 and 3 deal with the chemistry of drug biotransformation, describing both phase i asynthetic and phase ii synthetic. 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. The first drug metabolising polymorphism was described over 40.
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