Phase 1 drug metabolism pdf merge

Intestinal mucosa, kidney, lungs, skin and adrenals intestinal mucosa. Examples of phase i drug substrates are listed in table 4 1. Outline the phase 1 studies conducted to characterize the clinical pharmacology of a drug. 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. It is highly variable among drugs and depends on biological conditions. Although phase i drug metabolism occurs in most tissues, the primary and first pass site of metabolism occurs during hepatic circulation. Naproxen is also metabolised by phase ii metabolism directly to form a glycine. Enzymes that catalyze the biotransformation of drugs and xenobiotics are generally referred to as drugmetabolizing enzymes dmes. Phase ii drug metabolism 37 apparently exhibit a broad tissue distribution, although the liver is the major site of expression for many ugts. Factors affecting metabolism 1 the rate at which metabolism of toxic substances occurs is dependent on a variety of factors that can be categorized into two groups.

Phase i biotransformation reactions introduce or expose functional groups on the drug with the goal of increasing the polarity of the compound. 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. Types of phase 1 and phase 2 metabolism associated enzymes and cofactors. This quiz has been uploaded to scribd by medical student james lamberg.

Oct 23, 20 reduction, oxidation, hydrolysis, conjugation, glucuronidation, acetylation, sulfaction, mnemonics. These enzymes are found in high concentrations in the smooth endoplasmic reticulum of the liver. This learnatyourownpace online course is designed to provide scientists and regulatory professionals with a basic understanding of drug metabolism and its. Metabolomics is the study of some or all of these molecules 21, 36, 37, 73. Cannabinoid pharmacokinetics encompasses absorption after diverse routes of administration and from different drug formulations, analyte distribution throughout the body, metabolism by the liver and extrahepatic tissues, and elimination in the feces, urine, sweat, oral fluid, and hair. Phase i involves catabolic reactions that break down the toxicant. Reductive metabolism is carried out by various enzymes. The importance of a chapter on metabolism lies in the fact that drug interactions are based on these. 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. 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 conjugation of a drug can occur in the absence of phase 1 metabolism.

Product areas highlighted include our portfolio of reagents for drug transport, phase i metabolism, and drug conjugate analysis. Developing effective new drugs requires a thorough understanding of how the drugs will act once they are administered to the patient. The following are multiple choice questions in a style similar to those included in the usmle step 1. Phase i reactions include oxidation, reduction, and hydrolysis that are catalyzed by several enzymes including cytochrome p450. Phase 1 and phase 2 drug metabolism and bile acid production. Drug metabolism can be divided into the phase i reactions functionalisation and the phase ii reactions conjugation. While some drugs may undergo just phase 1 or phase 2, most undergo phase 1 followed by phase 2 in tandem. Biochemistry, biotransformation statpearls ncbi bookshelf.

Abnormal metabolism of fats lipids leading to abnormalities in the level of fats in the blood stream e. Types biotransformation reactions 2 types phase i non synthetic. Cannot predict bioavailability and halflife on just one pharmacokinetic parameter absorption. In phase ii more lipophilic groups are conjugated to the. Pdf on feb 1, 2005, p david josephy and others published phase i and phase ii drug metabolism.

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. 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. These groups can include glutathione, methyl or acetyl groups. Ingenuity pathway analysis of metabolomics data including. Parent drug watersoluble metabolitemore readily excreted from body enzyme drug metabolism involves the enzymatic. During phase 1, the inactive drug is made active by a set of drug metabolising enzymes. The body typically deals with a foreign compound by making it more watersoluble, to increase the rate of its excretion through the urine. The participation of phase ii drug metabolizing enzymes in the metabolism of clinically used drugs is shown in fig. Additional metabolism occurs in gastrointestinal epithelial, renal, skin, and lung tissues. Pdf phase i and phase ii ocular metabolic activities and the role. Absorbed drugs 3 changes metabolic changes by enzymes.

Phase 1 metabolism involves chemical reactions such as oxidation most common, reduction and hydrolysis. The metabolism of a drug or toxin in a body is an example of a biotransformation. Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. In part ii we will discuss the kinetics of drug metabolism and the relationship of kinetic data to the pharmacokinetics of a drug. The metabolism phase is absent for the few drugs that are not transformed. There are three possible results of phase 1 metabolism. What proportion percent of an oral drug gets from the gi tract into the blood.

The diester prodrugs were of special interest, since they combine an enhanced bioavailability and. Metabolism occurs in two phases, phase i metabolism, and phase ii metabolism. Phase ii of metabolism may or may not be preceded by phase i reactions. In phase 2, the active drug is made inactive and transformed in such a way that it is now suitable. These metabolic processes usually occur in the hepatocyte cytoplasm. In the intestine for example, several drug metabolising enzymes are presumed to decrease the bioavailability of orally administered drugs or to activate environmental carcinogens. Within cells, most phase i enzymes are located in the endoplasmic reticulum.

Introduction to phase i and ii metabolisms phase i. Phase ii biotransformations attach a hydrophilic moiety onto drugmetabolite. Hepatic metabolism continues to be the most important route of metabolism for foreign ingested chemicals xenobiotics and drugs. Other oxidative enzymes in drug metabolism include flavin monooxygenase and monoamine oxidase. 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. A more complex situation, combining product regioselectivity with substrate. Analyzing the function of genes encoding human drug metabolizing enzymes using. Phase 1 convert lipophilic molecules into more polar molecules hydrolysis, oxidation, reduction. These type of reactions most often abolish biological activity.

So while investing in a company based on its phase 1 drugs could be a smart idea, it could also end up backfiring. Molecular mechanism of phase i and phase ii drugmetabolizing. Often, phases 1 and 2 pathways work together to help in the removal of the xenobiotic. 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. Drug metabolism is basically a process that introduces hydrophilic functionailities onto the drug molecule to facilitate excretion. Conjugation reactions in which a polar molecule is linked to a suitable functional group on a drug or one of its phase 1 metabolites.

Cytochrome p450 cyp is a hemeprotein that plays a key role in the metabolism of drugs and other xenobiotics estabrook, 2003. Phase i metabolism consists of reduction, oxidation, or hydrolysis reactions. A population pk analysis estimated the tdm1 clearance and terminal elimination halflife as 0. Often these reactions involve the introduction of polar functional groups such as oh to drug molecules to make them more hydrophilic. I and phase ii reactions and may lead to limited oral bioavailability. Drug metabolism malay pandya medicinal chemistry k. Phase i reactions of drug metabolism involve oxidation, reduction, or hydrolysis of the parent drug, resulting in its conversion to a more polar molecule. Thus the drug is subjected to hepatic metabolism first pass effect before reaching the site of action. Liver is the primary site where majority of drug metabolism occurs in two phases. Therefore, amcbal culturing makes the heparg cells more suitable for testing metabolism and toxicity of drugs. Intestinal wall is rich in esterases and lipases enzymes. Metabolism is an essential pharmacokinetic process, which renders lipid soluble and nonpolar compounds to water soluble and polar compounds so that. Phase i metabolism includes oxidation, reduction, hydrolysis, and hydration and isomerization plus rarer misc. Cytochrome p450 enzymes are the most important class of enzymes in phase i metabolism.

Phase i and phase ii reactions of drug authorstream. The resulting product is too polar to recross membranes back into tissues and is readily excreted. Drug metabolism metabolic changes of drugs and related organic compounds describes the human metabolic processes of various functional groups found in therapeutic agents. 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. Xenobiotic metabolism, which includes drug metabolism, has become a major. Xenobiotic metabolizing enzymes have historically been grouped into the phase 1 reactions, in which enzymes carry out oxidation, reduction, or hydrolytic reactions, and the phase 2 reactions, in which enzymes form a conjugate of the substrate the phase 1 product table 3 1.

This work has focused on an approach, which combine in vitro and in vivo. Pdf while the mammalian eye is seldom considered an organ of drug. The hydroxylated product produced from phase 1 reactions can also be conjugated by conjugation enzymes to more hydrophilic products, easier to excrete. The content is so presented to allow the reader to compare various processes simultaneously and can easily memorize and learn about the topic. This article is part of the motley fools knowledge center, which was created. 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.

Ocular metabolism, drug delivery, drug design, phase i. Phase ii enzymes have attracted much less attention in clinical pharmacology than cytochromes p450 because drug interactions involving these enzymes are relatively fig. Petra jancovaa, pavel anzenbacherb eva anzenbacherova. 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 ii reactions involve conjugation with an endogenous substance eg, glucuronic acid, sulfate, glycine. Phase i biotransformations include oxidation, reduction, and hydrolysis reactions. This issue of biofiles features selected products from sigmaaldrich s drug metabolism platform. Noael established proceeded to phase 1 trials singledose well tolerated in multipledose phase 1 trials, subjects developed moderatesevere skin reactions. The correct answers can be found in link at the end of this post. 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. 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.

Learn phase 1 metabolism toxicity with free interactive flashcards. Conjugation is the joining of two substances to form s single molecule, which can increase. Part 1 of the article covers the basics of drug metabolism. Haplotype approaches combining the information of adjacent snps into composite. Tdm1 accumulation was not observed following multiple dosing. Two general categories of drug metabolism occur in the liver. 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. 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 ii reactions involve conjugation by coupling the drug or its metabolites to another molecule, such as glucuronidation, acylation, sulfate, or glicine. During phase i reactions hydrophobic molecules are transformed into more polar.

As explained in great detail in other chapters see 5. This is done by adding a functional group oh here on to the drug compound. 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 content has been concisely summarized to help understand various steps involved in the phase 1 and pase 2 metabolism processes of xenobiotics. 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 other words, the metabolites are pharmacologically inactive. Path of a drug after administration by any route, a drug will reach the blood stream as. Phase 2 metabolism involves conjugation that is, the attachment of an ionised group to the 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 especially by the cytochrome p450 group of enzymes, also called mixedfunction oxidases, reduction, deamination, and hydrolysis. 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.

Drug metabolism basics bioavailability and halflife. Cytochrome p450 cyp heme proteins are one of the largest superfamilies of. Overview definition consequences types phase iii in detail enzyme inductioninhibition first pass metabolism. These reactions serve to convert lipophilic drugs into more polar. Human cytochromes p450 associated with the phase 1 metabolism.

It is convenient to divide drug metabolism into two phases i and ii which sometimes. View the rest of my pharmacology videos in order be. Metabolism or biotransformation the conversion from one chemical form of a substance to another. Phase i reactions phase i reactions also termed nonsynthetic reactions may occur by oxidation, reduction, hydrolysis, cyclization, and decyclization addition of oxygen or removal of hydrogen, carried out by mixed function oxidases, often in the liver. The primary objective of drug metabolism is to facilitate a drug s excretion by increasing its water solubility hydrophilicity. If the metabolites of phase 1 reactions are sufficiently water soluble in. Choose from 198 different sets of phase 1 metabolism toxicity flashcards on quizlet. The term metabolism is commonly used probably because products of drug transformation are called metabolites.

Phase i reactions involve formation of a new or modified functional group or cleavage oxidation, reduction, hydrolysis. Phase ii enzymes undoubtedly play an important role in the detoxification of various xenobiotics. 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. Biotransformation is affected by the species of the test. Drug metabolism is the phase of biochemical transformation of the drug. Cytochrome p450 isozyme system play important role in phase i.