Human flavincontaining monooxygenase 3 hfmo3, a membranebound hepatic protein, belonging to the second most important class of phase 1 drug metabolizing enzymes, was immobilized in its active form on graphene oxide go for enhanced electrochemical response. Therefore, amcbal culturing makes the heparg cells more suitable for testing metabolism and toxicity of drugs. Pharm95a3 70% define phase i and phase ii reactions in. Drug metabolism phase 2 conjugation reactions medicinal chemistry 3rd stage 1.
Phase i metabolism may increase, decrease, or leave unaltered the drugs pharmacologic activity. The primary objective of drug metabolism is to facilitate a drug s excretion by increasing its water solubility hydrophilicity. The resulting product is too polar to recross membranes back into tissues and is readily excreted. Phase 1 reactions function to convert lipophilic drug molecules into more polar molecules by introducing or unmasking a polar functional group, such as oh or nh2. Phase i reactions convert the parent drug into more polar metabolites through introduction or exposing oh, sh, or nh2 functional groups. These enzymes are found in high concentrations in the smooth endoplasmic reticulum of the liver.
The biochemical reactions are known as metabolic pathways and involve enzymes that transform one substance into another substance, either. Jianda lu, jun xue, in critical care nephrology third edition, 2019. Phase i and phase ii reactions of drug authorstream. The term metabolism is commonly used probably because products of drug transformation are called metabolites. The liver is the principal, but not the sole, site of most drug metabolism in the body.
Drug metabolism is the chemical alteration of a drug by the body. Preclinical drug metabolism and pharmacokinetics studies play a key role. Reduction nadphcytochrome p450 reductase cytochrome p450 reductase also known as nadph. Typically, oxidation is the most common phase i reaction. Phase 2 conjugation of a drug can occur in the absence of phase 1 metabolism. The whole range of biochemical processes that occur within an organism, metabolism consists both of anabolism and catabolism the buildup and breakdown of substances, respectively. The number of patients will typically fall anywhere between 20 and 100.
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. 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. Introduction to phase i and ii metabolisms phase i. Noael established proceeded to phase 1 trials singledose well tolerated in multipledose phase 1 trials, subjects developed moderatesevere skin reactions. 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 1 studies are typically closely monitored and may be conducted in patients or normal volunteer subjects. Cyps are phase i metabolizing enzymes, cyps oxidize drugs by inserting one atom of oxygen into the drug molecule producing water as a by product number of families of cyps 12 families of cyps with 3 accounting for majority of drug metabolism. This biotransformation can be deterred by replacing the hydrogen at the paraposition and using fluorine as a. Metabolism is an essential pharmacokinetic process, which renders lipid soluble and nonpolar compounds to water soluble and polar compounds so that. This biotransformation can be deterred by replacing the hydrogen at the paraposition and using fluorine as a bioisostere. Phase i reactions are broadly grouped into three categories, oxidation, reduction, and hydrolysis. Pharm95a3 70% define phase i and phase ii reactions in drug metabolism. Phase i metabolism of drug candidates can be simulated in the laboratory using.
Drug metabolism is achieved through phase i reactions, phase ii reactions, or both. 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. It is highly variable among drugs and depends on biological conditions. Phase ii enzymes undoubtedly play an important role in the detoxification of various xenobiotics. 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 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 biotransform of drugs linkedin slideshare. The metabolism phase is absent for the few drugs that are not transformed. 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. The pharmacokinetic phase pharmacokinetic phase this phase describes the time course and disposition of a drug in the body, based on its absorption, distribution, metabolism and elimination. Noael established proceeded to phase 1 trials singledose well tolerated in multipledose phase 1 trials, subjects developed moderatesevere skin.
Drug metabolism is often considered during drug design. 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 metabolism may increase, decrease, or leave unaltered the drug s pharmacologic activity. In a phase 1 clinical trial, a small group of patients is recruited to try out a new drug. As explained in great detail in other chapters see 5. Phases of metabolism drug biotransformation could be classified into two phases 1. Metabolism is an essential pharmacokinetic process, which renders lipid soluble and nonpolar compounds to water soluble and. Phase 1 and phase 2 drug metabolism and bile acid production of heparg cells in a bioartificial liver in absence of dimethyl sulfoxide ruurdtje hoekstra, geert a. Drug metabolism phase 1 reactions oxidation cyp450 reduction phase 2 reactions conjugation reactions. Enzymes, substrates, and antibodies 12 drug conjugate analysis. Metabolism or biotransformation the conversion from one chemical form of a substance to another. 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.
The content is so presented to allow the reader to compare various processes simultaneously and can easily memorize and learn about the topic. 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 content has been concisely summarized to help understand various steps involved in the phase 1 and pase 2 metabolism processes of xenobiotics. 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. Conjugation reactions phase ii biotransformations attach a hydrophilic moiety onto drugmetabolite. Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through.
P450 oxidoreductase, p450 reductase, por, cpr, cypor, is a membranebound enzyme required for. Glutathione gsh or mercapturic acid conjugations 5. There are three possible results of phase 1 metabolism. Klingenberg first discovered cyp in 1954 during his research on steroid hormone metabolism, when he extracted a novel protein from hepatocytes.
Contains hepatic drugmetabolising enzymes cytochrome p450 referred to as cyp 1, 2. Occurs in the smooth endoplasmic reticulum ser of the liver cells 2. To describe phase 1 and phase 2 reactions, hepatic extraction ratio and its significance, first pass effect, enzyme induction and inhibition. Hexabarbital 10mgkg tolbutamide chloramphenicol 22. Principles of drug action part 2 1 rspt 2317 principles of drug action part 2. Pdf pathways of biotransformation phase i reactions.
Xenobiotic metabolism, which includes drug metabolism, has become a major pharmacolo. 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. These studies are designed to determine the metabolism and pharmacologic actions of. Pdf on feb 1, 2005, p david josephy and others published phase i and phase ii drug metabolism. Current concepts corina ionescu and mino r caira drug 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 drug s water solubility. Phase ii biotransformations attach a hydrophilic moiety onto drugmetabolite. Phase ii of metabolism may or may not be preceded by phase i reactions.
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 i metabolism includes oxidation, reduction, hydrolysis, and hydration and isomerization plus rarer misc. Induction of phase i, ii and iii drug metabolismtransport. The duration and intensity of drug action depend not only on the dose of the drug but also on the rates at which drugs are transformed to products that can be excreted readily by the kidney.
The involved chemical modifications incidentally decrease or increase a drug s pharmacological activity andor halflife, the most extreme example being the metabolic activation of inactive prodrugs into active drugs, e. View the rest of my pharmacology videos in order be. Often, phases 1 and 2 pathways work together to help in the removal of the xenobiotic. Examples of phase i drug substrates are listed in table 41. Phase i biotransformation reactions introduce or expose.
Drug metabolism is the phase of biochemical transformation of the drug. Human flavincontaining monooxygenase 3 on graphene oxide. Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. The primary objective of drug metabolism is to facilitate a drugs excretion by increasing its water solubility hydrophilicity. Glucuronidation sulfate glutathione glucine acetylation methylation generally these reactions generate compounds that are more water soluble aid in excretion.
For instance, a drug containing a benzene group may undergo phase i reactions e. 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. To improve protein stabilization and to ensure the electrocatalytic activity of the immobilized enzyme, didodecyldimethylammonium. What links here related changes upload file special pages permanent link page.
Phase 1 metabolism involves chemical reactions such as oxidation most common, reduction and hydrolysis. These reactions include hydrolysis, reduction, and oxidation. In other words, the metabolites are pharmacologically inactive. 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. Phase i and phase ii reactions of drug authorstream presentation. Induction of phase i, ii and iii drug metabolismtransport by. Occurs in the cytosolic fraction of the liver cells 4, 6. Phase i reactions include oxidation especially by the cytochrome p450 group of enzymes, also called mixedfunction oxidases, reduction, deamination, and hydrolysis. Phase i reactions include oxidation, reduction, and hydrolysis that are catalyzed by several enzymes including cytochrome p450. Phase 1 metabolism involves chemical reactions such as oxidation most. Although phase i drug metabolism occurs in most tissues, the primary and first pass site of metabolism occurs during hepatic circulation. The hydroxylated product produced from phase 1 reactions can also be conjugated by conjugation enzymes to more hydrophilic products, easier to excrete. Phase ii reactions involve conjugation by coupling the drug or its metabolites to another molecule, such as glucuronidation, acylation, sulfate, or glicine.
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. The cytochrome p450 enzyme system is particularly important because many different drugs also can induce or inhibit these enzymes, resulting in changing. Phase i reactions in microsomes are cata lyzed by a group of enzymes known. Proteins, antibodies, and modulators 4 phase i drug metabolism. Phase i biotransformation reactions introduce or expose functional groups on the drug with the goal of increasing the polarity of the compound. Infant posses poor glucuronidating ability because of a deficiency in glucuronyl transferase activity. Drug metabolizing enzymes dmes play central roles in the metabolism, elimination and detoxification of xenobiotics and drugs introduced into the human body. 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. Enzymes, substrates and inhibitors, and derivitization reagents 22 cover. These type of reactions most often abolish biological activity. During drug metabolism, the active, lipophillic chemicals are converted into derivatives that can be easily eliminated through the urine or bile. Metabolism process whereby a drug undergoes chemical modification to. Reactions that increase water solubility by conjugation of the drug molecule with a polar moiety such as glucuronate, acetate.
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