However, cytochrome p450 is localized in cellular membraness, whereas phase ii enzymes are, for the most part, in the cytoplasm water portion of cells. Phase ii of metabolism may or may not be preceded by phase i reactions. 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 i reactions convert the parent drug into more polar metabolites through introduction or exposing oh, sh, or nh2 functional groups. Phase ii metabolism involves conjugation of drugs or their metabolites with highly polar molecules. 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. Conjugation reactions phase ii biotransformations attach a hydrophilic moiety onto drug metabolite.
Phase i reactions of drug metabolism involve oxidation, reduction, or hydrolysis of the parent drug, resulting in its conversion to a more polar molecule. Drug metabolism in the liver university of washington. Among these, the most important as far as xenobiotic metabolism is concerned are the cytochromes p450 ec 1. The reactions catalyzed by these enzymes are classified into phase i and phase ii reactions.
Different in vitro methods, from subcelullar to organ range, and in vivo studies are applied for the clarification of drug metabolism. Drug metabolism and pharmacokinetics an overview european. However, phase ii metabolism remains relatively preserved in the elderly. Cytochromes p450 monooxygenation reactions are of major significance in drug metabolism and are mediated by various enzymes, which differ markedly in their structure and properties. Phase ii drug metabolism 37 apparently exhibit a broad tissue distribution, although the liver is the major site of expression for many ugts. Drug modifying enzymes are highly expressed in the small intestine and the liver. Many of the characteristics described earlier for cytochrome p450 also apply to these phase ii enzymes.
The most common phase ii drug metabolizing enzymes are udpglucuronosyltransferases ugts, sulfotransferases sults, nacetyltrans ferases nats, glutathione stransferases gsts, thiopurine smethyltransferases. Despite the fact that cyp enzymes play a major role in drug metabolism, it is important to consider phase ii drug metabolism in drug discovery so that toxic. Phase ii reactions involve conjugation of the drug with endogenous charged compounds such glutathionine, glucuronide, and. 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. This work is licensed under a creative commons attribution. Introduction to phase i and ii metabolisms phase i metabolism. In the plasma extracts, in addition to the parent drug and ndesmethyltamoxifen, a minor metabolite tamoxifen noxide was identified for the first time in human. The resulting product is too polar to recross membranes back into tissues and is readily excreted.
Four intact glucuronides of tamoxifen metabolites were. In the intestine for example, several drug metabolising enzymes are presumed to decrease the bioavailability of orally administered drugs or to activate environmental carcinogens. This chapter focuses on phase ii biotransformation reactions also called. 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. Find more similar flip pdfs like phase ii drug metabolism. In general, biotransformation reactions are divided into two broad. Udpglucuronosyltransferases ugts belong among the key enzymes of metabolism of various exogenous as well as. The analysis of metabolites in complex biological matrices is a challenging task therefore several. 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. 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. Phase ii biotransformations attach a hydrophilic moiety onto drug metabolite.
The ugt1a1, ugt1a3, ugt1a4, ugt1a6, ugt1a9, ugt2b7. Kidney also makes significant contribution in phase ii drug metabolism, but gst is the main conjugating enzyme in kidney. This renders these drugs water soluble and are easy to eliminate through the renal or biliary pathways. Phase 1 andor phase 2 some drugs undergo either phase 1 or phase 2 metabolism, but most undergo phase 1.
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. The cytochrome p450 proteins are monooxygenases that catalyze many reactions involved in drug metabolism, as well as the synthesis of cholesterol, steroids, and other. Often these reactions involve the introduction of polar functional groups such as oh to drug molecules to make them more hydrophilic. Drug metabolizing enzymes dmes play central roles in the metabolism, elimination and detoxification of xenobiotics and drugs introduced into the human body. Pdf on feb 1, 2005, p david josephy and others published phase i and phase ii drug metabolism. Different in vitro methods, from subcelullar to organ range, and in vivo studies are applied for the clarification of drug. Typically phase ii metabolism includes glucuronidation, acetylation, smethylation, and glutathione or sulfoconjugation of drugs. Some drugs undergo only phase i or phase ii reactions. Induction of phase i, ii and iii drug metabolismtransport by.
Product areas highlighted include our portfolio of reagents for drug transport, phase i metabolism, and drug conjugate analysis. Intestinal enterocytes participate in phase ii drug metabolism as well. The chemistry of drug metabolism needs an elaborate understand. 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. Understanding the metabolism of codeine is important for the. Phase i reactions, and the conjugation reactions are called phase ii reactions table a. The resulting product is too polar to recross membranes back. Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. Prebiotics are nondigestible substrates found in foods such. 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.
Ugts metabolize approximately 40% 70% of the 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. Phase i reactions are functionalization reactions that introduce polar chemical moieties. 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. Metabolic organs the chemistry of drug metabolism needs an elaborate understanding it is a fascinatingand a complicatedprocess. Metabolites formed in phase 2 are unlikely to be pharmacologically active. Cyp2c19 and cyp3a4 are the major players in the metabolism of benzodiazepines that undergo phase i metabolism figure 1. 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. Prebiotics and probiotics the next issue of biofiles will explore the functionality of prebiotics and probiotics. Phase i functionalization and phase ii conjugation. Pdf induction of phase i, ii and iii drug metabolism.
Phase ii reactions involve conjugation by coupling the drug or its metabolites to another molecule, such as glucuronidation, acylation, sulfate, or glicine. 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. The metabolism of a drug or toxin in a body is an example of a biotransformation. Drug metabolism is normally divided into two phases, phase i or functionalisation reactions and phase ii or conjugative reactions. Evaluation of active hexose correlated compound ahcc on. Induction of phase i, ii and iii drug metabolismtransport. Phase i metabolism tends to be reduced in the elderly, along with polypharmacy, predisposing elderly patients to cyp450 related interactions. 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. 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. Analysis of phase i and phase ii metabolites of tamoxifen. Phase ii enzymes undoubtedly play an important role in the detoxification of various xenobiotics. Sequential metabolism of 2,3,7trichlorodibenzopdioxin 2,3,7tricdd by cytochrome p450 and udpglucuronosyltransferase in human liver microsomes.
The ugt1a1, ugt1a3, ugt1a4, ugt1a6, ugt1a9, ugt2b7, and ugt2b15 belong among the main liver xenobiotic conjugating enzymes, whereas. This is because of the presenceof largeamounts of many varieties of enzymes. This proofofconcept study investigated phase ii biotransformation of 11 test substrates in fresh fullthickness human skin explants, a model containing all skin cell types. Chapters 2 and 3 deal with the chemistry of drug biotransformation, describing both phase i asynthetic and phase ii synthetic. Glucuronidation and sulfation in the flip pdf version. 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. Drug metabolism university of california, san diego. Phase ii biotransformations attach a hydrophilic moiety onto drugmetabolite. Glucuronidation and sulfation was published by on 20150511. 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. Phase i and phase ii biotransformation reactions deranged. Induction of phase i, ii and iii drug metabolismtransport by xenobiotics.
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. Phase i biotransformations include oxidation, reduction, and hydrolysis reactions. Phase 2 metabolism involves reactions that chemically change the drug or phase 1 metabolites. Pdf phase ii drug metabolizing enzymes researchgate. Phase i and phase ii biotransformation reactions catalyzed by xenobiotic biotransforming enzymes are generally divided into two groups. 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. Phase i and phase ii applied to describe types of drug metabolism was first used in the 1940s. This results in activation or inactivation of the parent drug. Phase i reactions include oxidation, reduction, and hydrolysis that are catalyzed by several enzymes including cytochrome p450.
Analytical methods for quantification of drug metabolites. Pdf phase ii biotransformation reactions also conjugation reactions generally serve as a detoxifying step in drug metabolism. In vitro drug metabolism, transport and drug interactions. 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. Drug metabolism can be divided into the phase i reactions functionalisation and the phase ii reactions conjugation. Analytical methods for quantification of drug metabolites in. Difference between phase i and phase ii metabolism compare. Udpglucuronosyltransferases, sulfotransferases, nacetyltransferases, glutathione stransferases and methyltransferases mainly thiopurine smethyl. 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. Introduction to phase i and ii metabolisms phase i. Environmental toxins, drug metabolism, and the microbiome. Pathways of drug metabolism are classified as either. Reduced metabolising capacity of phase ii enzymes can lead to toxic effects of clinically used drugs.
Drug metabolism in medicinal chemistry pharmafactz. Phase ii drug metabolising enzymes are mainly transferases. Theprimary site of drug metabolism is the smooth endoplasmic reticulum of the liver cell. The key organs in drug metabolism and excretion are the small intestine, the liver, and the kidneys. Aug 01, 2020 phase ii drug metabolism is a conjugation reaction that aims to introduce a hydrophilic moiety into the drug or phase i drug metabolite to increase the clearance of these xenobiotics. Although skin is the largest organ of the human body, cutaneous drug metabolism is often overlooked, and existing experimental models are insufficiently validated.
Results show that skin explants have significant capacity. In these conjugation reactions, drugs can be attached to any of the five polar compounds. Phase ii biotransformation reactions also conjugation reactions generally serve as a detoxifying step in drug metabolism. This is called conjugation and the product is called a conjugate. The chemical reactions normally associated with phase i and phase ii drug metabolism are given in table 1. Phases of drug metabolism phase i reactions convert parent compound into a more polar hydrophilic metabolite by adding or unmasking functional groups oh, sh.
1180 549 925 717 771 1026 781 74 1241 756 66 1735 336 845 1558 1633 1702 367 1423 1785 487 886 700 703 124 241 1619 942 219 885 1354 1016 1310 992 961