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. These enzymes are found in high concentrations in the smooth endoplasmic reticulum of the liver. If a drug is named you should know what it is used for ie carbamazepine is used in the treatment of epilepsy and its relationship to drug metabolism it is an inducer to cyp3a4, a substrate of cyp3a4 and can increase the clearance of coadministered cyp3a4 substrates. Learn vocabulary, terms, and more with flashcards, games, and other study tools. Phase i reactions involve hydrolysis, reduction and oxidation, exposing or introducing a functional group oh. It provides an invaluable introduction to the core areas of pharmacology and examines recent progress and advances in this fast moving field and its. Phase i and phase ii drugametabolizing enzymes are expressed.
Because the biliary epithelium, exposed to bileborne. View the rest of my pharmacology videos in order be. 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 of drug metabolism involve oxidation, reduction, or hydrolysis of the parent drug, resulting in its conversion to a more polar molecule. Phase ii of metabolism may or may not be preceded by phase i reactions. The chemical reactions normally associated with phase i and phase ii drug metabolism are given in table 1. Phase ii reactions involve conjugation by coupling the drug or its metabolites to another molecule, such as glucuronidation, acylation, sulfate, or glicine.
The drug metabolism process occurring in organs other than the figure 1. Therefore, amcbal culturing makes the heparg cells more suitable for testing metabolism and toxicity of drugs. Fast metabolism diet phase 1 portions portion sizes in fast metabolism diet phase 1 depend on the amount of weight you want to lose. 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. This issue of biofiles features selected products from sigmaaldrich s drug metabolism platform. Phase ii enzymes undoubtedly play an important role in the detoxification of various xenobiotics. Intestinal mucosa, kidney, lungs, skin and adrenals intestinal mucosa. Examples of phase i drug substrates are listed in table 4 1. These reactions include hydrolysis, reduction, and oxidation. The term metabolism is commonly used probably because products of drug transformation are called metabolites. Drug metabolism is the phase of biochemical transformation of the drug.
The absorption, metabolism, and excretion of ibrutinib were investigated in healthy men after administration of a single oral dose of 140 mg of 14clabeled ibrutinib. Hepatic metabolism continues to be the most important route of metabolism for foreign ingested chemicals xenobiotics and drugs. Phase i reactions convert the parent drug into more polar metabolites through introduction or exposing oh, sh, or nh2 functional groups. Phase ii biotransformations attach a hydrophilic moiety onto drug metabolite. The actual activity of a drug can be altered in one of 3 ways by phase 1 metabolism. On the other hand, these conjugations also play an essential role in the toxicity. Phase 1 drug metabolism functional conversion to polar metabolites in preparation for conjugation. Phase 1 metabolism involves chemical reactions such as oxidation most common, reduction and hydrolysis. 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.
The metabolism phase is absent for the few drugs that are not transformed. Drug metabolism principles and applications 100% online. The drug metabolism happening in the liver is termed as hepatic metabolism. In the intestine for example, several drug metabolising enzymes are presumed to decrease the bioavailability of orally administered drugs or to activate environmental carcinogens. Introduction of magnetic and supermagnetic nanoparticles in new approach of targeting drug delivery and cancer therapy application.
Drugs get metabolize through various types of metabplic reactions, in this video, there is explanation about these reactions with examples. Phase ii biotransformations attach a hydrophilic moiety onto drugmetabolite. Phase i metabolism is predominantly mediated by cyp2e1 and produces a reactive metabolite. 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. Fast metabolism diet phase 1, 2 and 3 ultimate guide for.
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. Metabolism is an essential pharmacokinetic process, which renders lipid soluble and nonpolar compounds to water soluble and. 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. 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 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 resulting product is too polar to recross membranes back into tissues and is readily excreted. Metabolism or biotransformation the conversion from one chemical form of a substance to another. Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through. Understanding the cyp system is essential for advanced practitioners aps, as the consequences of drug drug interactions can be profound. It is highly variable among drugs and depends on biological conditions. Drug biotransformation could be classified into two phases. Induction of phase i, ii and iii drug metabolismtransport by. Introduction to phase i and ii metabolisms phase i. These reactions are categorized as phase i and phase.
Safety considerations in phase 1 trials joseph toerner, md, mph deputy director for safety. This results in activation or inactivation of the parent drug. As explained in great detail in other chapters see 5. Phase i metabolism of drug candidates can be simulated in the laboratory using nonenzyme.
Often these reactions involve the introduction of polar functional groups such as oh to drug molecules to make them more hydrophilic. We know that elimination of apap involves phase i, ii, and iii metabolism. 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. 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. A common approach to produce humanized transgenic mouse models table 1 involves microinjection of a human transgene into fertilized zygotes and implantation of the eggs into pseudopregnant females. Phase i biotransformation reactions introduce or expose functional groups on the drug with the goal of increasing the polarity of the compound. Phase i biotransformations include oxidation, reduction, and hydrolysis reactions. Part 1 of the article covers the basics of drug metabolism. Introduction to phase i and ii metabolisms phase i metabolism. Product areas highlighted include our portfolio of reagents for drug transport, phase i metabolism, and drug conjugate analysis. 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. Absorption, metabolism, and excretion of oral 14c radiolabeled ibrutinib.
Drug metabolism can be divided into the phase i reactions functionalisation and the phase ii reactions conjugation. Drug metabolism is normally divided into two phases, phase i or functionalisation reactions and phase ii or con jugative reactions. If the metabolites of phase 1 reactions are sufficiently water soluble in. 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. There are three possible results of phase 1 metabolism. Reactions that increase water solubility by conjugation of the drug molecule with a polar moiety such as glucuronate, acetate. Pdf on feb 1, 2005, p david josephy and others published phase i and phase ii drug metabolism.
Difference between phase i and phase ii metabolism compare. 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. Phase 1 and phase 2 drug metabolism and bile acid production. Although phase i drug metabolism occurs in most tissues, the primary and first pass site of metabolism occurs during hepatic circulation.
Allied organic compounds williams, 1949 helped to establish the study of drug and. The content is so presented to allow the reader to compare various processes simultaneously and can easily memorize and learn about the topic. This study was a phase 1, openlabel, singlecenter, singledose study. These 3 enzymes are responsible for the metabolism of over 90% of drugs. 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.
However, benzene can also be oxidized by phase i metabolism to. The most important, in order, are cyp3a4, cyp2d6 and cyp2c9. Homework 1 drug metabolism 20 university of washington. Developing effective new drugs requires a thorough understanding of how the drugs will act once they are administered to the patient. 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. Outline the phase 1 studies conducted to characterize the clinical pharmacology of a drug. Phase 1 reactions phase 1 reactions are classified into oxidation, reduction and hydrolysis. It is convenient to divide drug metabolism into two phases i and ii. Tissue expression of drugmetabolizing enzymes influ ences susceptibility to drugs and carcinogens. Phase i metabolism absorption, distribution, metabolism and excretion adme. In addition to the liver, every biological tissue of the body has the ability to metabolize drugs. 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.
Phase i reactions include oxidation especially by the cytochrome p450 group of enzymes, also called mixedfunction oxidases, reduction, deamination, and hydrolysis. 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. 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. Phase i metabolism includes oxidation, reduction, hydrolysis, and hydration and isomerization plus rarer misc. Phase i reactions include oxidation, reduction, and hydrolysis that are catalyzed by several enzymes including cytochrome p450. Drug metabolizing enzymes and biotransformation reactions 1 nalia at penner, caoline r woodward and, chandra prakash a. The founders that carry human transgene can be used as breeders to establish homozygous transgenic mouse line. In other words, the metabolites are pharmacologically inactive. Furthermore, phase i metabolism occurs via unmasking or insertion of polar functional groups while phase ii metabolism. Alternatively, you can also get our printable fast metabolism diet phase 1 food list pdf through this link. Path of a drug after administration by any route, a drug will reach the blood stream as. During these reactions, certain groups are added so that the drug can undergo the second phase to produce conjugation products. Elimination irreversible removal of the drug from the body metabolism liver and intestine as major sites. Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems.
Therefore, this is the key difference between phase i and phase ii metabolism. The content has been concisely summarized to help understand various steps involved in the phase 1 and pase 2 metabolism processes of xenobiotics. Phase 1 metabolism involves chemical reactions such as oxidation most. Phase ii metabolism involves conjugating a drug or a metabolite from phase i with a chemical substituent. Humanized transgenic mouse models for drug metabolism and. Overview definition consequences types phase iii in detail enzyme inductioninhibition first pass metabolism. 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. These type of reactions most often abolish biological activity.384 1479 273 1136 430 1067 333 1306 1559 790 895 1261 565 157 348 256 1033 603 1554 1272 958 1247 334 513 726 412 512 890 1380 1406 272 1443 779 534 858 638 469