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. The primary site of drug metabolism is the liver, the organ that plays a major role in metabolism, digestion, detoxification, and elimination of substances from the body. This chapter focuses on phase ii biotransformation reactions also called. Drug metabolism phase 2 conjugation reactions medicinal chemistry 3rd stage 1. Phase i reactions involve hydrolysis, reduction and oxidation, exposing or introducing a functional group oh, nh 2, sh or cooh to slightly increase hydrophilicity. The liver is the principal, but not the sole, site of most drug metabolism in the body.
Phase ii of metabolism may or may not be preceded by phase i reactions. Phase ii enzymes undoubtedly play an important role in the detoxification of various xenobiotics. Pathways of biotransformation phase i reactions springerlink. Outline the role of drug metabolism in drug toxicity and carcinogenicity. 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. Enzymes in the liver are responsible for chemically changing drug components into substances known as metabolites. Phase ii drug metabolising enzymes are mainly transferases. Nonspecific esterases in liver, plasma, and gastrointestinal tract hydrolyzed.
Typically, oxidation is the most common phase i reaction. The formation of glucuronide conjugates is the most important detoxication pathway of the phase ii of drug metabolism in all vertebrates. Drug metabolisminteractions definition drug metabolism is the process by which the body breaks down and converts medication into active chemical substances. Interactions can lessen or magnify the desired therapeutic effect of a drug, or may cause unwanted or unexpected side effects. 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. Cytochrome p450, drug metabolism, toxicity, reactive metabolites. Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through. In subsequent phase ii reactions, these activated xenobiotic metabolites are conjugated with. Drug metabolism is the phase of biochemical transformation of the drug. The content has been concisely summarized to help understand various steps involved in the phase 1 and pase 2 metabolism processes of xenobiotics.
Furthermore, they significantly contribute to maintaining of homeostasis by binding, transport or inactivation of biologically active compounds such as hormones, bile acids, or. Phase 2 conjugation of a drug can occur in the absence of phase 1 metabolism. 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. The enzymes that catalyze these reactions can cause the substrate to. Biochemistry, biotransformation statpearls ncbi bookshelf. Phase ii conjugative enzymes metabolize drugs by attaching conjugating a more polar molecule to the original drug molecule to increase water solubility, thereby permitting more rapid drug excretion. Dissecting the reaction of phase ii metabolites of.
As most small molecule drugs are lipophilic in nature, drug metabolism converts these hydrophobic compounds into more water soluble compounds that can be excreted. Conjugation is very important, as this is the phase that increases the water solubility of the drug, which is needed to allow excretion of the drug. Fast mimicking of phase 1 and 2 metabolism of acetaminophen using the roxy ec system. Hence, drug metabolism is an important aspect of living systems. The term metabolism is commonly used probably because products of drug transformation are called metabolites. 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 reactions are broadly grouped into three categories, oxidation, reduction, and hydrolysis. Difference between phase i and phase ii metabolism. Classify mechanisms of drug metabolismphaseii and enzymes involved. The nats identified to date and involved in human drug metabolism include nat1 and nat2. Glutathione gsh or mercapturic acid conjugations 5. 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. What phase 1 reaction is mainly performed by the cytochrome p450 enzymes also called mixedfunction enzymes. Often, phases 1 and 2 pathways work together to help in the removal of the xenobiotic. Storage of sugar as glycogen and regulation of blood sugar levels. P450 oxidoreductase, p450 reductase, por, cpr, cypor, is a membranebound enzyme required for.
Fast mimicking of phase 1 and 2 metabolism of acetaminophen using the roxy ec system fast mimicking of phase 1 and 2 metabolism of acetaminophen using the roxy ec system fast mimicking of phase 1 and 2 metabolism of acetaminophen using the roxy ec system figure 1. Not as common as oxidative reactions generally the cyp450 enzymes are used in the presence of nadph three major types of reduction reactions pertinent to drug metabolism. Explain the effect of drug metabolism on drugs duration of action and activity. Phase i reactions include oxidation, reduction, and hydrolysis that are catalyzed by several enzymes including cytochrome p450. Enzymes involved in phase ii reactions are mainly located in the cytosol, except glucuronidation enzyme, which is also a microsomal enzyme. Petra jancovaa, pavel anzenbacherb eva anzenbacherova. Glucuronidation olinked moieties acyl, phenolic, hydroxy predominates the diversity in. Phase i biotransformations include oxidation, reduction, and hydrolysis reactions. Phase ii biotransformation reactions also conjugation reactions generally serve as a detoxifying step in drug metabolism. Homework 1 drug metabolism 20 university of washington.
The second phase of drug metabolism is conjugation, which is a phase i metabolite joining to another compound. Drug metabolism phase i and phase 2 usmlefasttrack. The scheme of typical glucuronidation reactions is shown in figure 1. The primary objective of drug metabolism is to facilitate a drugs excretion by increasing its water solubility hydrophilicity. Phase 1 reactions are almost nonexistent in the fetuses of laboratory animals. Yields a polar, watersoluble, metabolite that is often still active. Phase i and phase ii biotransformation reactions catalyzed by xenobiotic biotransforming enzymes are generally divided into two groups. Phase i reaction definition of phase i reaction by. It is highly variable among drugs and depends on biological conditions. Phase i reactions, and the conjugation reactions are called phase ii reactions table a. The enzymes responsible for these conjugative or addon. Unlike p450, phase ii reactions are concerted reactions that. Drug metabolism can be divided into the phase i reactions functionalisation and the phase ii reactions conjugation. Sult1 and 2 are most important in the metabolism of drugs.
Phase i reaction definition of phase i reaction by medical. Phase i functionalisation reactions phase ii conjugation reactions isomerisation e. 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. In humans, approximately 4070% of all clinical drugs are subjected to glucuronidation reactions.
Introduction to drug metabolism philadelphia university. Enzymology and molecular mechanisms of drug metabolism reactions. Recently, a third phase of metabolism has been proposed phase iii, in recognition of the role of membrane transporters on the biliary excretion of drugs and their metabolites, as well as the ef. Phase i and phase ii reactions of drug authorstream presentation.
Phase ii reactions involve conjugation by coupling the drug or its metabolites to another molecule, such as glucuronidation, acylation, sulfate, or glicine. Phase 1 and phase 2 drug metabolism and bile acid production. Phase i reactions of drug metabolism involve oxidation, reduction, or hydrolysis of the parent drug, resulting in its conversion to a more polar molecule. The cytochrome p450 enzyme system is particularly important because many different drugs also can induce or inhibit these enzymes, resulting in changing.
Postulated routes of formation of 3 and 4 hydroxy mepivacaine and their urinary. Despite these and other shortcomings 91, the traditional classification in phase 1 and 2 reactions remains helpful to structure the wide range of reactions and this classification is used below. Phase 1 reactions produce functional groups that can participate in phase 2 reactions. P450 oxidoreductase, p450 reductase, por, cpr, cypor, is a membranebound enzyme required for electron transfer to cytochrome p450 in the microsome of the. Pathways of drug metabolism drug metabolism is divided. 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. Metabolism is an essential pharmacokinetic process, which renders lipid soluble and nonpolar compounds to water soluble and polar compounds so that. Phase ii biotransform of drugs linkedin slideshare. 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. Oct 23, 20 drug metabolism phase i and phase 2 usmlefasttrack. 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. The metabolism phase is absent for the few drugs that are not transformed.
This process is experimental and the keywords may be updated as the learning algorithm improves. This involves attaching an endogenous substrate to the drug or to the phase i metabolite. Cytochrome p450s and other enzymes in drug metabolism and. Often these reactions involve the introduction of polar functional groups such as oh to drug molecules to make them more hydrophilic. Two general categories of drug metabolism occur in the liver.
At this level, most clinicians begin to take more of. As explained in great detail in other chapters see 5. Precautions drugs can interact with other drugs, foods, and beverages. One of the most common modifications is hydroxylation catalysed by the cytochrome. 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. What drugs metabolism has phase 2 preceding phase 1. Drug metabolism is the chemical alteration of a drug by the body. 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. Phase i and phase ii reactions of drug authorstream. Drug metabolism human liver microsome aldehyde oxidase sequential metabolism reversible metabolism these keywords were added by machine and not by the authors. The role of these various enzyme activities in the liver is to convert fat soluble toxins into water soluble substances that can be excreted in the urine or the bile depending on the particular characteristics of the end product. Learn vocabulary, terms, and more with flashcards, games, and other study tools.
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 i biotransformation reactions introduce or expose functional groups on the drug with the goal of increasing the polarity of the compound. Phase i reactions involve hydrolysis, reduction and oxidation, exposing or introducing a functional group oh, nh 2. 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 convert the parent drug into more polar metabolites through introduction or exposing oh, sh, or nh2 functional groups. 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 metabolism drug metabolism is the anabolic and catabolic breakdown of drugs by living organisms. Metabolism or biotransformation the conversion from one chemical form of a substance to another. An important point to note is that some drugs dont undergo phase i metabolic reaction but instead are directly deactivated by phase ii reactions. Although phase i drug metabolism occurs in most tissues, the primary and first pass site of metabolism occurs during hepatic circulation. Reduction nadphcytochrome p450 reductase cytochrome p450 reductase also known as nadph. Pathways of drug metabolism drug metabolism is divided into two phases. The hydroxylated product produced from phase 1 reactions can also be conjugated by conjugation enzymes to more hydrophilic products, easier to excrete. Therefore, amcbal culturing makes the heparg cells more suitable for testing metabolism and toxicity of drugs.
Metabolism occurs in two phases, phase i metabolism, and phase ii metabolism. Introduction to phase i and ii metabolisms phase i. A drug can ultimately undergo further metabolism during phase iii. Phase ii metabolism conjugation of drugs and other xenobiotics with a range of different molecules including glucuronic acid, sulfate, amino acids, acetyl groups, methyl groups and glutathione properties of the enzyme families catalyzing these conjugation reactions. Phase ii reactions include glucuronidation, sulfation, acetylation, methylation. This form of metabolism involves oxidation with the cyp450 enzymatic family.
Metabolism is an essential pharmacokinetic process, which renders lipid soluble and nonpolar compounds to water soluble and. Phase ii metabolism involves the introduction of a hydrophilic endogenous species, such as glucuronic acid or sulfate, to the drug molecule. Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. 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.
547 1244 1128 337 195 1124 725 315 94 135 645 106 180 158 1346 186 1365 1231 1076 560 1048 23 906 1420 587 416 26 1322 80 379 1011 713 647 1472 1453 491 896 1432 1165 1364