Phase 2 conjugation of a drug can occur in the absence of phase 1 metabolism. Would you expect a significant drug drug interaction between tramadol and a cyp3a4 inducer. The enzymes involved in metabolism are present in many tissues but generally are more concentrated in the liver. Pathways of drug metabolism drug metabolism is divided into two phases.
Drug metabolism phase i almost any drug can undergo modi. Safety considerations in phase 1 trials joseph toerner, md, mph deputy director for safety. Drug and other xenobiotic metabolism occur through three phases, namely, phase i, phase ii. Phase i reactions of drug metabolism involve oxidation, reduction, or hydrolysis of the parent drug, resulting in its conversion to a more polar molecule. From the department of pharmacology, vanderbilt university, nashville. Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. Metabolic reductions, hydrolysis, phase 2 metabolism. In humans, approximately 4070% of all clinical drugs are subjected to glucuronidation reactions metabolized by ugts 3. Sult1 and 2 are most important in the metabolism of drugs found in liver, kidney, intestine, in cytosol catalyze the sulfation of alcohols roh phenols main group of substrates, aroh arylamines arnh. When the drug molecule is oxidized, hydrolyzed, or covalently attached to a hydrophilic species, the whole molecule becomes more hydrophilic, and is excreted more easily. Drug metabolism in the liver university of washington. Phase ii enzymes undoubtedly play an important role in the detoxification of various xenobiotics. Reduced metabolising capacity of phase ii enzymes can lead to toxic effects of clinically used drugs. Therefore, these two articles cover much of the same ground.
It is highly variable among drugs and depends on biological conditions. Pdf introductiongenetic polymorphismseffects of age on drug. The hydroxylated product produced from phase 1 reactions can also be conjugated by conjugation enzymes to more hydrophilic products, easier to excrete. Theprimary site of drug metabolism is the smooth endoplasmic reticulum of the liver cell. Understanding the exact mechanism of each extract of an herb that affects drugs absorption, distribution, metabolism, and excretion adme properties is incomplete at the moment. Drugmetabolizing enzymes and transporters present in extrahepatic tissues, such as nasal mucosa and the respiratory tract, have been particularly discussed. In the intestine for example, several drug metabolising enzymes are presumed to decrease the bioavailability of orally administered drugs or to activate environmental carcinogens. Drug enzyme metabolism involves phase i reactions oxidation. 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. The resulting product is too polar to recross membranes back into tissues and is readily excreted. Cytochrome p450 isozyme system play important role in phase i. The participation of phase ii drug metabolizing enzymes in the metabolism of clinically used drugs is shown in fig. A more complex situation, combining product regioselectivity with substrate. The metabolism phase is absent for the few drugs that are not transformed.
Often, phases 1 and 2 pathways work together to help in the removal of the xenobiotic. Phase ii biotransformations attach a hydrophilic moiety onto drug metabolite. Meta systems combining a docking, 3dqsar, mo, and b a number of enzymes and other. Oct 23, 20 reduction, oxidation, hydrolysis, conjugation, glucuronidation, acetylation, sulfaction, mnemonics. Petra jancovaa, pavel anzenbacherb eva anzenbacherova.
Show the structure of the sulfate metabolite of parent drug. Phase ii reactions involve conjugation by coupling the drug or its metabolites to another molecule, such as glucuronidation, acylation, sulfate, or glicine. Induction of phase i, ii and iii drug metabolismtransport by. Drug metabolizing enzymes dmes play central roles in the metabolism, elimination and detoxification of xenobiotics and drugs introduced into the human body. 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.
Homework 1 drug metabolism 20 university of washington. This issue of biofiles features selected products from sigmaaldrich s drug metabolism platform. Metabolism or biotransformation the conversion from one chemical form of a substance to another. 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. Induction of phase i, ii and iii drug metabolismtransport. Phase ii drug metabolizing enzymes play an important role in biotransformation of endogenous compounds and xenobiotics to more easily excretable forms as well as in the metabolic inactivation of pharmacologically active compounds. Phase ii biotransformations attach a hydrophilic moiety onto drugmetabolite. Phase ii enzymes have attracted much less attention in clinical pharmacology than cytochromes p450 because drug interactions involving these enzymes are relatively fig. In phase ii more lipophilic groups are conjugated to the.
Sarita sharma assistant professor of pharmacology mumbai 2. Drug metabolism is basically a process that introduces hydrophilic functionailities onto the drug molecule to facilitate excretion. Some drugs just undergo one or the other but the majority will undergo phase 1 and then phase 2 sequentially. Phase ii drug metabolism 37 apparently exhibit a broad tissue distribution, although the liver is the major site of expression for many ugts. 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. Pdf on feb 1, 2005, p david josephy and others published phase i and phase ii drug metabolism. Phase ii of metabolism may or may not be preceded by phase i reactions. Contains hepatic drug metabolising enzymes cytochrome p450 referred to as cyp 1, 2. 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. During these reactions, certain groups are added so that the drug can undergo. 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. As marketed antiallergic drugs include both racemates and enantiomers, aspects of stereoselective absorption, distribution, metabolism. Phase i metabolism definition of phase i metabolism by. Pdf in vitro assays are increasingly being used in drug metabolism. Phase i reactions convert the parent drug into more polar metabolites through introduction or exposing oh, sh, or nh2 functional groups. Drug metabolism 1 is an extremely important area of research, as side effects of a. This biotransformation can be deterred by replacing the hydrogen at the paraposition and using fluorine as a. Preclinical drug metabolism and pharmacokinetics studies play a key role in lead identification and. Drug metabolism typically results in the formation of a more hydrophilic compound that is readily excreted by the liver, kidney, andor gut. Topics on drug metabolism 2 bioavailability humans. This is because of the presenceof largeamounts of many varieties of enzymes. Special section on emerging novel enzyme pathways in drug.
This article is very similar to xenobiotic metabolism, and in fact, drug metabolism is a sub category of xenobiotic metabolism. Metabolism is an essential pharmacokinetic process, which renders lipid soluble and nonpolar compounds to water soluble and polar compounds so that. There are three possible results of phase 1 metabolism. Drug metabolism and oxidative stress longdom publishing sl. Some patients metabolize a drug so rapidly that therapeutically effective blood and tissue concentrations are not reached. To this end, this special section on emerging novel enzyme pathways in drug metabolism will highlight a number of advancements that have recently been reported. For instance, a drug containing a benzene group may undergo phase i reactions e. Drug metabolism involves chemical biotransformation of drug molecules by enzymes in. It may be difficult to distinguish between the two concepts, since many if not most xenobiotics can act as drugs in the body. 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.
Phase 2 biotransformation reaction animated biology with arpan. Metabolism of drugs is usually divided into phase 1 and phase 2. The chemistry of drug metabolism needs an elaborate understanding it is a fascinatingand a complicatedprocess. Drug metabolism university of california, san diego. These enzymes are found in high concentrations in the smooth endoplasmic reticulum of the liver. During phase i metabolism, drug molecules are transformed through oxidation or reduction of hydrolysis reactions by the action of a family of enzymes called the cytochrome p450 cyp or microsomal enzyme system. Occurs in the smooth endoplasmic reticulum ser of the liver cells 2. Hydrolysis, reduction, and oxidation 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 term metabolism is commonly used probably because products of drug transformation are called metabolites. Wilkinson at the department of pharmacology, vanderbilt university, 542 robinson research bldg. The biotransformation of xenobiotics by xenobioticmetabolizing enzymes xmes may be classified into phase i and phase ii reactions. Developing effective new drugs requires a thorough understanding of how the drugs will act once they are administered to the patient. Haplotype approaches combining the information of adjacent snps into. 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. Learn vocabulary, terms, and more with flashcards, games, and other study tools. Phase i metabolism includes oxidation, reduction, hydrolysis, and hydration and isomerization plus rarer misc.
Metabolism is an essential pharmacokinetic process, which converts lipid soluble and nonpolar compounds to water soluble and polar compounds so that they are excreted by various. Drugs can be metabolized by oxidation, reduction, hydrolysis, hydration, conjugation, condensation, or isomerization. Phase i biotransformation reactions introduce or expose functional groups on the drug with the goal of increasing the polarity of the compound. Phase i hereby mainly covers destructive processes, while phase ii reactions are more related to conjugation glucuronidation, sulfation, methylation, acetylation, or glutathione processes.
The general intention is to demonstrate that the metabolism of a drug is a primary concern throughout. In other words, the metabolites are pharmacologically inactive. Phases of metabolism drug biotransformation could be classified into two phases 1. 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 functionalisation reactions phase ii conjugation reactions isomerisation e. Drug metabolism can be divided into the phase i reactions functionalisation and the phase ii reactions conjugation. Phase 1 metabolism involves chemical reactions such as oxidation most common, reduction and hydrolysis.
Ugt enzymes are responsible for the metabolism of many xenobiotics e. The following are multiple choice questions in a style similar to those included in the usmle step 1. Drug metabolism is often considered during drug design. This quiz has been uploaded to scribd by medical student james lamberg. Similar to drug drug interactions, the multicomponent herbs can exert their effects on pharmacokinetics and consequently lead to herb drug interactions hdis. These type of reactions most often abolish biological activity. Examples of phase i drug substrates are listed in table 41.
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. Drug metabolism is normally divided into two phases, phase i or functionalisation reactions and phase ii or conjugative reactions. This learnatyourownpace online course is designed to provide scientists and regulatory professionals with a basic understanding of drug metabolism and its. Combining several of these approaches may allow the use of one to validate the other. 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 biotransformations include oxidation, reduction, and hydrolysis reactions. Phase i reactions include oxidation, reduction, and hydrolysis that are catalyzed by several enzymes including cytochrome p450. View the rest of my pharmacology videos in order be. The phase i metabolism article is poorly written and contributes little that isnt already covered in this main article. Current trends in drug metabolism and pharmacokinetics. Although phase i drug metabolism occurs in most tissues, the primary and first pass site of metabolism occurs during hepatic circulation. Pdf strategies for using in vitro screens in drug metabolism. Ontogeny of phase i metabolism of drugs allegaert 2019. It is convenient to divide drug metabolism into two phases i and ii which sometimes.
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. Product areas highlighted include our portfolio of reagents for drug transport, phase i metabolism, and drug conjugate analysis. Drug metabolism phase 2 conjugation reactions medicinal chemistry 3rd stage 1. Phase 1 reactions phase 1 reactions are classified into oxidation, reduction and hydrolysis. Goller,3 dieter lang,4 jens kunze,1 bernard testa,5 ian d. The pathways involved in drug metabolism are commonly classified in phase i or phase ii reactions. Introduction to phase i and ii metabolisms phase i. Metabolism or biotransformation it is the enzymatic conversion from one chemical form of a substance to another. During drug metabolism, the active, lipophillic chemicals are converted into derivatives that can be easily eliminated through the urine or bile. Pathways of drug metabolism drug metabolism is divided into. Often these reactions involve the introduction of polar functional groups such as oh to drug molecules to make them more hydrophilic. 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. What is different about phase 2 reactions is that unlike in phase i where drug metabolites often retain pharmacological activity, phase 2 reactions pretty. Phase ii of drug metabolism mainly involves glucuronidation catalyzed by udp.
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