The content has been concisely summarized to help understand various steps involved in the phase 1 and pase 2 metabolism processes of xenobiotics. In addition to the liver, every biological tissue of the body has the ability to metabolize drugs. 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 get metabolize through various types of metabplic reactions, in this video, there is explanation about these reactions with examples. Phase i metabolism may increase, decrease, or leave unaltered the drugs pharmacologic activity. Overview definition consequences types phase iii in detail enzyme inductioninhibition first pass metabolism. Pathways of biotransformation phase ii reactions springerlink. The content is so presented to allow the reader to compare various processes simultaneously and can easily memorize and learn about the topic. Phase 1 metabolism involves chemical reactions such as oxidation most common, reduction and hydrolysis. 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. These reactions are catalysed by transferase enzymes such as glutathione stransferases. 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.
During these reactions, certain groups are added so that the drug can undergo the second phase to produce conjugation products. Mechanistically, these conjugation reactions proceed via two subsequent, enzymatically catalyzed reactions. 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 metabolism is normally divided into two phases, phase i or functionalisation reactions and phase ii or conjugative reactions. Examples of phase i drug substrates are listed in table 41. It is highly variable among drugs and depends on biological conditions. The first drug metabolising polymorphism was described over 40. View the rest of my pharmacology videos in order be. The metabolism phase is absent for the few drugs that are not transformed. Difference between phase i and phase ii metabolism compare. This results in activation or inactivation of the parent drug. These modified compounds are then conjugated to polar compounds in phase ii reactions. Phase 1 reactions function to convert lipophilic drug molecules into more polar molecules by introducing or unmasking a polar functional group, such as oh or nh2. Phase 1 metabolism involves chemical reactions such as oxidation most.
Introduction to phase i and ii metabolisms phase i. These reactions include hydrolysis, reduction, and oxidation. The first drug metabolising polymorphism was described over 40 years ago for acetylation. These enzymes are found in high concentrations in the smooth endoplasmic reticulum of the liver. Homework 1 drug metabolism 20 university of washington. 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. Quizlet flashcards, activities and games help you improve your grades.
Phase i reactions include oxidation especially by the cytochrome p450 group of enzymes, also called mixedfunction oxidases, reduction, deamination, and hydrolysis. Drug metabolism is the phase of biochemical transformation of the drug. 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. 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 2 drug metabolism enzymatic conjugation reaction in the intestine and liver. Phasei drug metabolism drug metabolism cytochrome p450. 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. Phase i biotransformations include oxidation, reduction, and hydrolysis reactions. Xenobiotic metabolism, which includes drug metabolism, has become a major pharmacolo. In phase i, enzymes such as cytochrome p450 oxidases introduce reactive or polar groups into xenobiotics. Overview definition consequences types phase iii in detail. These reactions are catalyzed by udpglucuronosyltransferases ugt1a1 and 1a6 and sulfotransferases sult1a1, 1a34, and. 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. Reactions that increase water solubility by conjugation of the drug molecule with a polar moiety such as glucuronate, acetate.
In the intestine for example, several drug metabolising enzymes are presumed to decrease the bioavailability of orally administered drugs or to activate environmental carcinogens. 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. Medicinal chemistry drug metabolism december 3rd, 2014 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. 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. Recently, a third phase of metabolism has been proposed phase iii, in recognition of the role of membrane transporters on the. Drug metabolism is normally divided into two phases, phase i or functionalisation reactions and phase ii or con jugative 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. Most of the drug is eliminated by glucuronidation and sulfation. Often these reactions involve the introduction of polar functional groups such as oh to drug molecules to make them more hydrophilic. Drug metabolizing enzymes and biotransformation reactions.
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. Sep 22, 2017 metabolism is the protective biochemical process by which our bodies alter xenobiotics either enzymatically or nonenzymatically. Phase i reactions include oxidation, reduction, and hydrolysis that are catalyzed by several enzymes including cytochrome p450. 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. Phasei drug metabolism free download as powerpoint presentation. This chapter focuses on phase ii biotransformation reactions also called. Although phase i drug metabolism occurs in most tissues, the primary and first pass site of metabolism occurs during hepatic circulation. Phase i and phase ii reactions of drug authorstream. Phase ii reactions involve conjugation by coupling the drug or its metabolites to another molecule, such as glucuronidation, acylation, sulfate, or glicine. Drug metabolism can be divided into the phase i reactions functionalisation and the phase ii reactions conjugation. Phase ii enzymes undoubtedly play an important role in the detoxification of various xenobiotics. Phase ii of metabolism may or may not be preceded by phase i reactions. The resulting product is too polar to recross membranes back into tissues and is readily excreted. Learn vocabulary, terms, and more with flashcards, games, and other study tools.
Phase 1 reactions phase 1 reactions are classified into oxidation, reduction and hydrolysis. The first studies of apap metabolism and activation were published more than forty years ago. Conjugation reactions phase ii biotransformations attach a hydrophilic moiety onto drugmetabolite. Phase i reactions, and the conjugation reactions are called phase ii reactions table a. However, the compound itself has no pharmacological activity. The actual activity of a drug can be altered in one of 3 ways by phase 1 metabolism. Introduction to phase i and ii metabolisms phase i metabolism. 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. Drug metabolic process involves two phases, the occurrence of which may. Phase i reactions include oxidation, reduction, and hydrolysis that are catalyzed by several enzymes. 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. Metabolism occurs in two phases, phase i metabolism, and phase ii metabolism. Phase 1 transformations reactions of functionalization involve the creation of a functional group or the modification of an existing one by oxidation, reduction, or.
Phase i biotransformation reactions introduce or expose functional groups on the drug with the goal of increasing the polarity of the compound. 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. 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. A process in which nonmicrosomal enzymes convert esters and amides into carboxylic acids and alcohols, which are water soluble substances that can be excreted through renal processing 1, 4, 6. Phase i metabolism includes oxidation, reduction, hydrolysis, and hydration and isomerization plus rarer misc. Phase 1 drug metabolism functional conversion to polar metabolites in. As explained in great detail in other chapters see 5. In other words, the metabolites are pharmacologically inactive. Phase i reactions convert the parent drug into more polar metabolites through introduction or exposing oh, sh, or nh2 functional groups. This report describes the chemical reactions of drug metabolism and explains how they occur in vivo. There are three possible results of phase 1 metabolism. The final product of phase i metabolism may possess two different results.
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