In contrast to phase i metabolism, very little is known about the phase ii metabolism of classic cannabinoids. Glucuronic acid from greek sweet and urine is a uronic acid that was first isolated from urine hence the name. Glucuronidation is the most common phase ii reaction. Glucuronic acid is a product of glucose metabolism, and conjugation with glucuronic acid forms glucuronide metabolites. In contrast with glucuronic acid and sulfate, glycine and glutamine are not converted to activated coenzymes. Due to glucuronic acid conjugation, bioactive compounds become inactive, and lipophilic substances become more hydrophilic, which enhances their excretion to urine and bile. Udpglucuronosyltransferases ugts 52 catalyze the formation of betadglucuronides from a large variety of xenobiotics by their reaction with udp glucuronic acid udpga. Learn phase 2 metabolism drug with free interactive flashcards. Conjugation with glycine, glutamine and other amino acids glycine and glutamine are used by mammalian systems to conjugate carboxylic acids, particularly aromatic acids. Glucuronide conjugation is one of the most important and common phase ii reactions. Substrates for glucuronide formation are phenols, alcohols, carboxylic acids, amines, hydroxylamines, and mercaptans. Divided into three parts with nine chapters, the book contains the literature of authors who have incessantly conducted research on this kind of acid.
Carboxylic acids, alcohols, phenols, and hydroxylamine can undergo glucuronidation. Amino acid conjugation drug metabolism derick mussen. The formation of statin glucuronide and statin lactone in human liver microsomes exhibited modest intersubject variability 3 to 6fold. Thus the administered drug can be excreted in one foreign ingested chemical of the following forms. Reactions that increase water solubility by conjugation of the drug molecule with a polar moiety such as glucuronate, acetate, or sulfate cyp isozymes cytochrome p450 enzyme species eg, cyp2d and cyp3a4 that are responsible for much of drug metabolism. Conjugation of carboxylic acids with amino groups of gly, glut, taurine a. 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. Amino acid conjugation is a significant metabolic route for a number of carboxylic acids and involves the formation of an amide bond between the xenobiotic acylcoa and the amino acid. 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 i reactions convert the parent drug into more polar metabolites through introduction or exposing oh, sh, or nh2 functional groups. Enterohepatic circulation delays the elimination of xenobiotics and can increase toxicity. Two types of glucuronides, with an ether or an ester bond, were characterized. 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 ii metabolites, originating from the conjugation with glucuronic acid of phase i metabolites containing free hydroxy or carboxylic functions, were isolated.
In humans, conjugation with glucuronic acid is the most important phase ii metabolic reaction of steroidal compounds. Basic concepts in pharmacokinetics university of warwick. Determination of glucuronic acid conjugation is the most important route for investigations of metabolism of drug, while the glucuronide samples are rarely obtained. This occurs via the catalysis of glucuronosyltransferases ugts. Jan, 2018 cellular mechanism for phase 2 metabolism. Glucose6phosphate is converted to glucose1phosphate by phosphoglucomutase. The product then reacts with utp to form udpg by the help of the enzyme udpg pyrophosphorylase. Glucuronidation is an important phase ii metabolism reaction that is catalyzed by udpglucuronosyltransferases ugts. The salts of glucuronic acid are known as glucuronates. Both compounds have been proposed as antiinflammatory agents. 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. Because glucuronic acid is highly polar, its conjugation with less polar compounds such as steroids, bilirubin, and some drugs can reduce their activity and make. Glucuronic acid is a uronic acid that was first isolated from urine. The glucuronic acid conjugation of acyclic aliphatic alcohols.
Morphine, acetaminophen, hydroxycoumarin, salacylic acid. Glycine is the amino acid most frequently used for conjugation of small aromatic acids reaction a in figure 19, while a few glutamine conjugates reaction b in figure 19 have been characterized in. Choose from 500 different sets of phase 2 metabolism drug flashcards on quizlet. The conjugated metabolite has larger size and increased water solubility, which allows for secretion into the bile or urine. The present study characterized the kinetics of the separate r and s enantiomers of lorazepam by human liver microsomes.
View enhanced pdf access article on wiley online library html view. Glucuronoconjugated metabolites have been conventionally studied by using. The present study characterized the kinetics of the separate r and s enantiomers of lorazepam by human liver microsomes hlms and by a panel of recombinant human udp. Here, we also talk aboutdrug metabolism and the essential factors that underpin this central discipline in. Optimizing glucuronic acid production using tea fungus on grape juice by response surface methodology. One example is the nglucuronidation of an aromatic amine, 4aminobiphenyl, by ugt1a4 or ugt1a9 from human, rat, or mouse liver. The widely used hypnosedativeanxiolytic agent r,slorazepam is cleared predominantly by conjugation with glucuronic acid in humans, but the enantioselective glucuronidation of lorazepam has received little attention. Drug molecules having functional groups like oh cooh, nh 2 undergo conjugation with endogenous substances like glucuronic acid, acetate, acetylation, sulfate sulfuric acid ester formation and various amino acids. Mpa conjugation variation between cat liver microsomes was threefold for total conjugation and for phenol glucosidation, sixfold for phenol. The primary objective of drug metabolism is to facilitate a drugs excretion by increasing its water solubility hydrophilicity. Drugs can be metabolized by oxidation, reduction, hydrolysis, hydration, conjugation, condensation, or isomerization. In this chapter, we will concentrate on the most important conjugation reactions, namely glucuronide conjugation, sulfoconjugation, acetylation, amino acid conjugation, glutathione conjugation and.
Glucuronic acid conjugation sulfate conjugation glutathione conjugation conjugation with amino acids. Bilirubin is conjugated with d glucuronic acid to form mono and diglucuronides. Phase i reactions include oxidation, reduction, and hydrolysis that are catalyzed by several enzymes including cytochrome p450. Glucuronidation is an important phase ii reaction catalyzed by the udpglucuronosyltransferases ugts, ugts are enzymes involved in a number of metabolic processes, including phase ii drug metabolism 35% of therapeutic drugs undergo conjugation with glucuronic acid prior to elimination. Jun 16, 2015 their function is to catalyze the covalent linkage of glucuronic acid from udp glucuronic acid to an accepting functional group on the molecule, a process referred to as glucuronidation. Drug metabolism can be divided into the phase i reactions. In this article we will discuss about the metabolic reaction and importance of glucuronic acid. Introduction to phase i and ii metabolisms phase i. This results in activation or inactivation of the parent drug. Thus, evaluation of the ability of new drug candidates to inhibit ugt1a1catalyzed bilirubin glucuronidation in vitro has become common practice.
Drug metabolizing enzyme s dme s are a diverse group of proteins that. By means of an lcnmr technique, the glucuronide structure was established to be a 1oacylbetadglucuronide conjugate of the statin acid. Phase ii metabolites seem to be mainly conjugates of the phase i metabolites with glucuronic acid, catalyzed by the activity of udpglucuronosyltransferases ugts. Glucuronic acid is donated by uridine diphosphate glucuronic acid udpga, which serves as an endogenous substrate for the enzyme glucuronyl transferase. The glucuronic acid molecule is used in this reaction. Comparative metabolism of mycophenolic acid by glucuronic acid and glucose conjugation in human, dog, and cat liver microsomes. The conjugated drugs are water soluble and pharmacologically inactive. Pdf glucuronidation is a phase ii metabolic process and one of the most common. In addition to increasing water solubility, conjugation with glucuronic acid has another important function, it inactivates the drug. In humans, glucuronic acid is often linked to toxic or poisonous substances to allow for subsequent elimination, and to hormones to allow for easier transport. Apr 01, 2009 in contrast to phase i metabolism, very little is known about the phase ii metabolism of classic cannabinoids. Ring c analogues the 6 oh of morphine are not required for analgesic.
Introduction to phase i and ii metabolisms phase i metabolism. Glucuronic acid binding site, based on docking to apo enzyme. Udp glucuronic acid glucuronic acid linked via a glycosidic bond to uridine diphosphate is an intermediate in the process and is formed in the liver. 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. In humans, a major metabolite of the atypical antipsychotic olanzapine in the plasma and in the urine was found to be an n glucuronide. Glucuronic acid definition of glucuronic acid by medical. Get a printable copy pdf file of the complete article 1.
The enzymes involved in metabolism are present in many tissues but generally are more concentrated in the liver. Modulation of metabolic detoxification pathways using foods. It involves the trans fer of the glucuronic acid group from udpglucuronic acid udpgluca to an acceptor. As anticipated, a number of nucleophilic functional groups such as hydroxyl, phenolic, acyl, primary secondary and tertiary amino, etc. Pdf optimizing glucuronic acid production using tea fungus. Glucuronic acid binding site, based on docking to apo enzyme 2b7structure indicates. Why is the conjugation of glucuronic acid the most common conjugation pathway. With many drugs, hydroxylation by cytochrome p450 or some other phase i reaction precedes conjugation with glucuronic acid, glutathione, or another functional group. In this chapter, we will concentrate on the most important conjugation reactions, namely glucuronide conjugation, sulfoconjugation, acetylation, amino acid. Medicinal chemistry understanding drug metabolism december 3rd, 2014 medicinal chemistry this page focusses onstructural changes that occur when drugs undergo biotransformation and its importance in drug design and medicinal chemistry. Impaired bilirubin conjugation, caused by inhibition of ugt1a1, can result in clinical consequences, including jaundice and kernicterus.
The chemical properties of the drug contain two hydroxyl groups which allow the conjugate group to bind to thereby, inactivating the drug s therapeutic effects. Bilirubin, an end product of heme catabolism, is primarily eliminated via glucuronic acid conjugation by ugt1a1. It is found in many gums such as gum arabic, xanthan, and kombucha tea and is important for the metabolism of. O phase 2 aspirin conjugates glycine or glucuronic acid to make several ionised metabolites that can then be excreted in the urine. In the body, acetylsalicylic acid is rapidly deacetylated to form salicylic acid. It is derived from glucose, a common carbohydrate sugar that is the primary source of energy for cells. Conjugation of hydroxylamines with carboxylic acid group, ser, pro a.
Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. Unexpectedly, the glucuronic acid moiety was linked through a nitrogen of the benzodiazepine nucleus of olanzapine by way of a secondary amine linkage, rather than through a nitrogen on the piperazine substituent of the nucleus, to give a quaternary. Homework 1 drug metabolism 20 university of washington. Conjugation of glucuronic acid to nucleophilic functional groups in chemical entities results in formation of glucuronides. Ugts are a very broad and divers group of enzymes and count as the most significant group of conjugation enzymes in xenobiotic metabolism, qualitatively because glucuronic acid can be coupled to a large diversity of functional groups and quantitatively because of the large and divers number of substrates that are formed. Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. Ether and ester glucuronic acid conjugates of lacidipine. Pdf drug glucuronidation in clinical psychopharmacology. Biotransformation of drugs drug metabolism alcohol. Learn vocabulary, terms, and more with flashcards, games, and other study tools.
Udpglucuronyl transferase conjugates the glucuronic acid to the drug. The prodrug undergoes phase ii metabolism by the process of glucuronidation, the addition of a conjugate group known as glucuronic acid that is catalysed by the enzyme ugt. Conjugation of arylacetic acids in man and rhesus monkey. Glucuronidation is a major drugmetabolizing reaction. Recall, ga conjugation is a phase 2 metabolism reaction in which ga acts as a conjugation molecule and binds to a substrate. Drug metabolism reactions are divided into two phases. The constituent glycyrrhizic acid, is a conjugate of two molecules, namely glucuronic acid and glycyrrhetinic acid.
For example, glucuronosyltransferase ugt transfers udp glucuronic acid to the drug to create a conjugated compound. Glucuronide and glucoside conjugation of mycophenolic acid by human liver, kidney and intestinal microsomes m shipkova, 1, c p strassburg, 2 f braun, 3 f streit, 1 hj grone, 4 v w armstrong, 1 r h tukey, 5, 6 m oellerich, 1 and e wieland 1. Concentration of udp glucuronic acid was increased 257% by glycyrrhiza roots and 484% by glycyrrhizin. Use of lcmsms for the open detection of steroid metabolites. Major metabolites of salicylic acid are its acyl and phenolic glucuronide conjugates. The metabolism of phenobarbital illustrates a pattern that applies to many other drugs as well. Glucuronidation occurs primarily in the liver but can occur in other tissues, such as the small intestine 86, 87. These data indicate that gr and glycyrrhizin activated glucuronidation and thus suggest the.
Reaction of 2 phase drug metabolism type of reaction glucuronic conjugation sulfate conjugation. Acetylsalicylic acid aspirin is a common nonsteroidal antiinflammatory drug used for treatment of pain and arthritis. In this reaction, glucuronic acid is added directly to the toxicant or its phase i metabolite. Glucuronide and glucoside conjugation of mycophenolic acid. Sep 22, 2017 metabolism is the protective biochemical process by which our bodies alter xenobiotics either enzymatically or nonenzymatically. Desvenlafaxineglucuronide is the final metabolite of conjugation reaction with glucuronic acid. Endogenous reagent or substrate uridinediphosphate of glucuronic acid udpgt 3phosphoadenosine5phosphosulfate paps acetylcoa glutathione. Chemistry, biochemistry, pharmacology, and medicine focuses on the study of glucuronic acid, particularly its physiological role in different fields. Both of these metabolites are fairly polar and are effectively excreted through the kidneys. Comparative metabolism of mycophenolic acid by glucuronic. Conjugation with glucuronic acid is the most abundant phaseii reaction see 5.
First, in a series of reactions, the cosubstrate udp. Xenobiotic substrate carboxylic acid, alcohol, phenol, amine. In phase ii of phenobarbital metabolism, the hydroxyl group just introduced is conjugated either with glucuronic acid by udpglucuronosyltransferases, or with sulfate by sulfotransferases. Ndesvenlafaxineglucuronide is an end product of a 2step metabolic reaction that starts with oxidation by cyp 3a4 to produce ndesvenlafaxine, which is conjugated with glucuronic acid to create ndesvenlafaxineglucuronide. Udpg is oxidized to uridine diphosphoglucuronic acid by. Drug metabolizing enzymes and biotransformation reactions. This is because the glucuronide metabolites are inactivate. Markey laboratory of neurotoxicology nimh, nih dec. Because glucuronic acid is highly polar, its conjugation with less polar compounds such as steroids, bilirubin, and some drugs can reduce their activity and make them more watersoluble, thus facilitating renal excretion. Comparative metabolism of mycophenolic acid by glucuronic acid and glucose conjugation in human, dog, and cat liver microsomes j. Phenol combines with d glucuronic acid to form phenylglucuronide. Phase ii reactions are catalyzed by transferases that require cofactors endogenous for the reactions. Showing metabocard for dglucuronic acid hmdb0000127. Species variations in the pathways of drug metabolism.
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