Cyp2c19 and cyp3a4 are the major players in the metabolism of benzodiazepines that undergo phase i metabolism figure 1. Phase i and phase ii biotransformation reactions deranged. Phase ii biotransformations attach a hydrophilic moiety onto drug metabolite. 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 2 nhydroxy compounds rnhoh cofactor 3phosphoadenosine5phosphosulfate, paps is in limited supply, drug can overwhelm the system. Pdf phase ii drug metabolizing enzymes researchgate. Drug metabolism in the liver university of washington. Oct 16, 2020 the major site of metabolism in the body is the liver 48, and metabolism occurs in two stages. Phase i reactions involve hydrolysis, reduction and oxidation, exposing or introducing a functional group oh, nh 2, sh or cooh to slightly increase hydrophilicity. Phase ii metabolism phase ii is usually the true detoxification of drugs occurs mostly in cytosol gives products that are generally water soluble and easily excreted includes sugar conjugation, sulfation, methylation, acetylation, amino acid conjugation, glutathione conjugation. Prebiotics are nondigestible substrates found in foods such. Production of human phase 1 and 2 metabolites by wholecell. Phase 2 metabolism involves reactions that chemically change the drug or phase 1 metabolites. Metabolism of drugs is usually divided into phase 1 and phase 2.
Some drugs just undergo one or the other but the majority will undergo phase 1 and then phase 2 sequentially. In vitro drug metabolism, transport and drug interactions. During these reactions, certain groups are added so that the drug can undergo. Drug metabolism can be divided into the phase i reactions functionalisation and the phase ii reactions conjugation. Products are generally more water soluble these reactions products are ready for renal excretion there are many complementary, sequential and competing pathways phase i and phase ii metabolism are a coupled interactive system interfacing with endogenous metabolic pathways. Cytochrome p450s and other enzymes in drug metabolism and. Phase i and phase ii biotransformation reactions catalyzed by xenobiotic biotransforming enzymes are generally divided into two groups.
Drug modifying enzymes are highly expressed in the small intestine and the liver. Usually, one enantiomer tends to be much more active then other. The enzymes responsible for phase 2 drug metabolism belong primarily to five enzyme families. Phase i reactions convert the parent drug into more polar metabolites through introduction or exposing oh, sh, or nh2 functional groups. Udpglucuronosyltransferases, sulfotransferases, nacetyltransferases, glutathione stransferases and methyltransferases mainly thiopurine smethyl. Pdf phase ii biotransformation reactions also conjugation reactions generally serve as a detoxifying step in drug metabolism. Most of the tissues and organs in our body are well equipped with diverse and various dmes including phase i, phase ii metabolizing enzymes a. Phase i reactions usually precede phase ii reactions. However, phase ii metabolism remains relatively preserved in the elderly. Drug metabolism phase 2 conjugation reactions medicinal chemistry 3rd stage 1.
In these conjugation reactions, drugs can be attached to any of the five polar compounds. Phase 2 metabolism conjugates the drug to hydrophilic substances, such as glucuronic acid, sulfate, glycine, or glutathione. The most important phase 2 reaction is glucuronidation, catalyzed by the enzyme uridine diphosphate glucuronosyltransferase ugt. Glucuronidation produces molecules that are highly hydrophilic and therefore easily. 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 all, phase 2 metabolism accounts for approximately 30% percent of all metabolites. Several enzymes catalyze conjugations of chemicals with low m r compounds already in the cells, or they catalyze hydrolysis reactions. Product areas highlighted include our portfolio of reagents for drug transport, phase i metabolism, and drug conjugate analysis. Molecular mechanism of phase i and phase ii drug metabolizing enzymes. Intestinal enterocytes participate in phase ii drug metabolism as well. Drug metabolism in medicinal chemistry pharmafactz.
The purpose of metabolism is to detoxify a drug, eliminate a drug or activate a drug. Dec 12, 2009 the journey from molecular target and early drug lead to the clinic is an arduous one with many hurdles to cross prior to developing a successful clinical candidate. 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. Phase ii metabolism involves conjugation of drugs or their metabolites with highly polar molecules. Allied organic compounds williams, 1949 helped to establish the study of drug and. Drug metabolism and pharmacokinetics an overview european. Mimicry of this important drug metabolism process is a topic of current research, and various. Ugts metabolize approximately 40% 70% of the xenobiotics. The major site of metabolism in the body is the liver 48, and metabolism occurs in two stages. Phase ii enzymes undoubtedly play an important role in the detoxification of various xenobiotics. Impact of gut microbiota on intestinal and hepatic levels. Chapters 2 and 3 deal with the chemistry of drug biotransformation, describing both phase i asynthetic and phase ii synthetic.
Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. In metabolism there are two phases, phase i and phase ii. Molecular mechanisms of drug metabolism in the critically ill oxford. 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. Phase ii drug metabolism 37 apparently exhibit a broad tissue distribution, although the liver is the major site of expression for many ugts. Theprimary site of drug metabolism is the smooth endoplasmic reticulum of the liver cell. Induction of phase i, ii and iii drug metabolismtransport by xenobiotics. 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. 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. Production of human phase 1 and 2 metabolites by whole. Metabolic organs the chemistry of drug metabolism needs an elaborate understanding it is a fascinatingand a complicatedprocess. Prediction of the metabolites resulting from phase 1. In the intestine for example, several drug metabolising enzymes are presumed to decrease the bioavailability of orally administered drugs or to activate environmental carcinogens. Introduction to phase i and ii metabolisms phase i.
Pharmacogenetics of phase i and phase ii drug metabolism. Difference between phase i and phase ii metabolism compare. Phase i pathways in liver microsomes are catalyzed by cytochrome p450 enzymes and include aromatic. For drugs of drug related material might be more appropriate triggers safety concern. This study describes the application of lcmsms to the determination of phase i and phase ii metabolites of tamoxifen in urine and plasma samples of breast cancer patients. Impact of gut microbiota on intestinal and hepatic levels of. Phase i biotransformations include oxidation, reduction, and hydrolysis reactions. Phase ii of metabolism may or may not be preceded by phase i reactions.
Phase ii reactions involve conjugation by coupling the drug or its metabolites to another molecule, such as glucuronidation, acylation, sulfate, or glicine. These enzymes have often been collectively referred to as phase ii reactions p450 and other oxidations being phase i, although such a convention is no longer. Udpglucuronosyltransferases ugts, glutathione stransferases gsts, sulfotransferases sults, nacetyltransferases nats, and methyltransferases mts. Phase ii reactions involve conjugation of the drug with endogenous charged compounds such glutathionine, glucuronide, and. Phase i reactions, and the conjugation reactions are called phase ii reactions table a. Pathways of drug metabolism are classified as either. The majority of drugs metabolized in vivo are oxidized in phase 1 of its metabolism pathway by enzymes from the cytochrome p450 cyp 450 family. Find more similar flip pdfs like phase ii drug metabolism. The high rate of attrition of drug molecules has forced drug researchers to pay greater attention to drug metabolism and pharmacokinetics dmpk of lead molecules at even the earliest stages of drug discovery.
Drug metabolism is a process that facilitates drug clearance by 1 increasing solubility, or 2 being responsible for converting prodrugs to their active drug form along with the formation of potentially toxic metabolites. Using immunoblotting, we compared levels of phase 2 enzymes in liver, small intestine, cecum, and colon of germfree and control rats reassociated with rat intestinal microbiota. This results in activation or inactivation of the parent drug. In the first chapter, the principles underlying drug absorption, distribution, metabolism and elimination are described, with drug metabolism highlighted within the context of these fundamental processes.
The resulting product is too polar to recross membranes back. Cytochrome p450s and other enzymes in drug metabolism. Induction of phase i, ii and iii drug metabolismtransport. This chapter focuses on phase ii biotransformation reactions also called. Induction of phase i, ii and iii drug metabolismtransport by. Phase ii drug metabolising enzymes are mainly transferases.
Phase i reactions include oxidation, reduction, and hydrolysis that are catalyzed by several enzymes including cytochrome p450. The ugt1a1, ugt1a3, ugt1a4, ugt1a6, ugt1a9, ugt2b7. 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. Drug metabolism changes in the elderly liver decrease in hepatic blood flow often associated with decreased first pass effect phase i metabolism decreased phase ii metabolism generally preserved table 23. Phase 1 reactions phase 1 reactions are classified into oxidation, reduction and hydrolysis. The reactions catalyzed by these enzymes are classified into phase i and phase ii reactions. Glucuronidation and sulfation was published by on 20150511. In addition, colonic levels were studied after association with human intestinal microbiota. Drug metabolizing enzymes dmes play central roles in the metabolism, elimination and detoxification of xenobiotics and drugs introduced into the human body. Introduction to phase i and ii metabolisms phase i metabolism. Oct 26, 2014 2 outline introduction history phases of metabolism phase i metabolism cytochrome p family phase ii metabolism first pass metabolism ante drug microsomal enzyme induction role of metabolism in drug discovery dr swaroop hs copyighted 3.
Udpglucuronosyltransferases ugts belong among the key enzymes of metabolism of various exogenous as well as. The resulting product is too polar to recross membranes back into tissues and is readily excreted. Following this, a conjugation step can take place in phase 2, involving for example glutathione gsh 2. The ugt1a1, ugt1a3, ugt1a4, ugt1a6, ugt1a9, ugt2b7, and ugt2b15 belong among the main liver xenobiotic conjugating enzymes, whereas. Analysis of phase i and phase ii metabolites of tamoxifen in. Prebiotics and probiotics the next issue of biofiles will explore the functionality of prebiotics and probiotics. Four intact glucuronides of tamoxifen metabolites were.
Glucuronidation and sulfation in the flip pdf version. Sequential metabolism of 2,3,7trichlorodibenzopdioxin 2,3,7tricdd by cytochrome p450 and udpglucuronosyltransferase in human liver microsomes. Phase ii metabolism is terminology coined by rt williams, whereby a compound is first subject tooxidation reduction or hydrolysis phase i reactions, which may be associated with bioactivation, andthen the functional group created is conjugated. The key organs in drug metabolism and excretion are the small intestine, the liver, and the kidneys. The glutathione transferases gsts studied, gastrointestinal glutathione peroxidase gpx2, both epoxide hydrolases. Phase 1 u phase i reactions u often involve mixed function oxidase system u cytochrome p450 plays most important role u often introduce a reactive group to the molecule u adds or exposes functional groups eg. This is because of the presenceof largeamounts of many varieties of enzymes. Some drugs undergo only phase i or phase ii reactions. Kidney also makes significant contribution in phase ii drug metabolism, but gst is the main conjugating enzyme in kidney. The two enantiomers present in racemic mixture may differ in pharmacological activity. 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. Pathways of biotransformation phase i reactions springerlink. Phase ii reactions include glucuronidation, sulfation, acetylation, methylation, conjugation with glutathione, and conjugation with amino acids glycine, taurine and glutamic acid that strongly increase hydrophilicity. Phase ii biotransformation reactions also conjugation reactions generally serve as a detoxifying step in drug metabolism.
Glutathione gsh or mercapturic acid conjugations 5. For example, phase i metabolism converts acetonitrile to hoch2cn, which rapidly dissociates. In a number of cases, phase i metabolites may be excreted prior to conjugation. Phase ii reactions include glucuronidation, sulfation, acetylation. Drug metabolism university of california, san diego. Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through. Oh, sh, nh 2, cooh allowing excretion or permitting compound to undergo phase ii reactions. Phase i metabolism tends to be reduced in the elderly, along with polypharmacy, predisposing elderly patients to cyp450 related interactions. Analysis of phase i and phase ii metabolites of tamoxifen. An example of this is morphine, that is metabolized to morphine3 glucuronide m3g and morphine.
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