The resulting product is too polar to recross membranes back into tissues and is readily excreted. Drug metabolism a fascinating link between chemistry and biology nikhil taxak and prasad v bharatam keywords drug metabolism, chemistry, cyp450, toxicity. Drug metabolism principles and applications drug metabolism is how organisms break down drugs. Phase i biotransformation reactions introduce or expose functional groups on the drug with the goal of increasing the polarity of the compound. 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. 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. Although phase i drug metabolism occurs in most tissues, the primary and first pass site of metabolism occurs during hepatic circulation.
Reactions that increase water solubility by conjugation of the drug molecule with a polar moiety such as glucuronate, acetate, or. 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 involve hydrolysis, reduction and oxidation, exposing or introducing a functional group oh, nh 2, sh or cooh to increase reactivity. As most small molecule drugs are lipophilic in nature, drug metabolism converts these hydrophobic compounds into more water soluble compounds that can be excreted. The high rate of attrition of drug molecules has forced drug researchers to pay greater attention to drug metabolism and pharmacokinetics dmpk of lead molecules at even the earliest stages of drug discovery. Drug metabolism can be divided into the phase i reactions functionalisation and the phase ii reactions conjugation. 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. Nikhil is a dst inspire fellow and is pursuing phd in niper, mohali. Drug metabolism and pharmacokinetics an overview european. 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. Phasei drug metabolism free download as powerpoint presentation.
Preclinical drug metabolism and pharmacokinetics studies play a key role in lead identification and. Induction of phase i, ii and iii drug metabolismtransport. Reactions that increase water solubility by conjugation of the drug molecule with a polar moiety such as glucuronate, acetate. Learn vocabulary, terms, and more with flashcards, games, and other study tools. Biotransformation drug metabolism linkedin slideshare. Introduction of phase i, phase ii drug metabolizing enzymes and phase iii drug transporters drug metabolizing enzymes dmes play central roles in the metabolism, elimination andor detoxification of xenobiotics or exogenous compounds introduced into the body meyer, 1996. These reactions include hydrolysis, reduction, and oxidation. The primary objective of drug metabolism is to facilitate a drugs excretion by increasing its water solubility hydrophilicity. A primer for bioanalytical chemists, part i in the face of advancing technology in combinatorial synthesis and high throughput screening, the drug discovery process continues to evolve. Phase i metabolism is predominantly mediated by cyp2e1 and produces a reactive metabolite. The first drug metabolising polymorphism was described over 40 years ago for acetylation. Genetic polymorphisms, drug metabolism and drug concentrations. 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.
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. Product areas highlighted include our portfolio of reagents for drug transport, phase i metabolism, and drug conjugate analysis. 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. We know that elimination of apap involves phase i, ii, and iii metabolism. Conjugation reactions phase ii biotransformations attach a hydrophilic moiety onto drugmetabolite. Phasei drug metabolism drug metabolism cytochrome p450. Introduction to phase i and ii metabolisms phase i metabolism. Prebiotics are nondigestible substrates found in foods such. Drug metabolism is carried out by phase i nonsynthetic reactions and phase ii conjugation reactions.
Metabolism or biotransformation it is the enzymatic conversion from one chemical form of a substance to another. 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. To understand the full clearance mechanisms of the drug and its metabolites in humans typically single dose, healthy males n46, at. Phase ii drug metabolism 37 apparently exhibit a broad tissue distribution, although the liver is the major site of expression for many ugts. 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.
Phase i reactions include oxidation especially by the cytochrome p450 group of enzymes, also called mixedfunction oxidases, reduction, deamination, and hydrolysis. 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. Drug metabolism consists of two classes of reactions, known as phase i and phase ii. In other words, the metabolites are pharmacologically inactive. 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 2 metabolism involves reactions that chemically change the drug or phase 1 metabolites. Introduction to phase i and ii metabolisms phase i. 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. Overview definition consequences types phase iii in detail enzyme inductioninhibition first pass metabolism. 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. There are three possible results of phase 1 metabolism. Often these reactions involve the introduction of polar functional groups such as oh to drug molecules to make them more hydrophilic. It provides an invaluable introduction to the core areas of pharmacology and examines recent progress and advances in. Pdf on feb 1, 2005, p david josephy and others published phase i and phase ii drug metabolism.
Allied organic compounds williams, 1949 helped to establish the study of drug and. Phase ii biotransformations attach a hydrophilic moiety onto drugmetabolite. Developing effective new drugs requires a thorough understanding of how the drugs will act once they are administered to the patient. 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. Difference between phase i and phase ii metabolism compare. The kidney readily eliminates the resulting watersoluble conjugate, or the bile if the molecular weight exceeds 300. Phases of metabolism drug biotransformation could be classified into two phases 1. Absorption, metabolism, and excretion of oral 14c radiolabeled ibrutinib. Phase i biotransformations include oxidation, reduction, and hydrolysis reactions. This results in activation or inactivation of the parent drug. The ugt1a1, ugt1a3, ugt1a4, ugt1a6, ugt1a9, ugt2b7, and ugt2b15 belong among the main liver xenobiotic conjugating enzymes, whereas ugt1a7, ugt1a8, and ugt1a10 are predominan tly extrahepatic ugt forms. Phase i reactions include oxidation, reduction, and hydrolysis that are catalyzed by several enzymes including cytochrome p450. Formally, biotransformation of xenobiotics as well as endogenous compounds is subdivided into phase i and phase ii reactions. Typically, oxidation is the most common phase i reaction.
Phase ii reactions involve conjugation by coupling the drug or its metabolites to another molecule, such as glucuronidation, acylation, sulfate, or glicine. Phase i reactions are broadly grouped into three categories, oxidation, reduction, and hydrolysis. 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. Drug metabolism is normally divided into two phases, phase i or functionalisation reactions and phase ii or con jugative reactions. The mechanisms of drug metabolism the process of drug metabolism may be defined as the biochemical modification of pharmaceutical agents by different enzymatic pathways to prepare the substance for elimination from the body 3. Phase 1 drug metabolism functional conversion to polar metabolites in preparation for conjugation. Phase i reactions of drug metabolism involve oxidation, reduction, or hydrolysis of the parent drug, resulting in its conversion to a more polar molecule. His hobbies include playing table tennis and reading novels. 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. Phase 1 metabolism involves chemical reactions such as oxidation most common, reduction and hydrolysis. Chapters 2 and 3 deal with the chemistry of drug biotransformation. Induction of phase i, ii and iii drug metabolismtransport by xenobiotics. 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.
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. This chapter focuses on phase ii biotransformation reactions also called. 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. His research pertains to drug metabolism and toxicity. Drug metabolism principles and applications 100% online. These enzymes are found in high concentrations in the smooth endoplasmic reticulum of the liver. 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. Phase i metabolism includes oxidation, reduction, hydrolysis, and hydration and isomerization plus rarer misc. Phase i reactions convert the parent drug into more polar metabolites through introduction or exposing oh, sh, or nh2 functional groups. The complications of drugdrug interactions mainly depends on the induction or inhibition of metabolic enzymes drug metabolism can be divided into two distinct categories. Reactions which introduce or unmask hydrophilic groups in the drug structure functionalisations. 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.
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. Metabolism is an essential pharmacokinetic process, which converts lipid soluble and nonpolar compounds to water soluble and polar compounds so that. Induction of phase i, ii and iii drug metabolismtransport by. Phase i and phase ii biotransformation reactions catalyzed by xenobiotic biotransforming enzymes are generally divided into two groups. These type of reactions most often abolish biological activity. 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. Sarita sharma assistant professor of pharmacology mumbai 2. Prebiotics and probiotics the next issue of biofiles will explore the functionality of prebiotics and probiotics.
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