The enzymes of phase i metabolism, most notably the cytochrome p450 enzymes, only slightly increase water solubility of the drug molecule and does not always increase it enough to facilitate. Induction of phase i, ii and iii drug metabolismtransport. In contrast to humans, all rats and mice were equol producer, independent of their sex. Therefore, benzene metabolism was studied in isolated rodent hepatocytes. Furthermore, substantial differences were observed between daidzein and genistein metabolism.
Phase ii reactions involve conjugation by coupling the drug or its metabolites to another molecule, such as glucuronidation, acylation, sulfate, or glicine. Pdf on feb 1, 2005, p david josephy and others published phase i and phase ii drug metabolism. Conjugation reactions glucuronidation, methylation, sulphation, acetylation, gluthathione conjugation, glycine conjugation 4 ugt1a and 2b isoforms key determinants of pharmacokinetics, efficacy and safety of many pediatric drugs rapid and continuous differentiation and maturation of metabolic functions limited knowledge. Phase ii the second stage of metabolism is an anabolic reaction that consists of conjugating enzymes responsible for increasing the water solubility of substrates by the addition of a polar substituent 1.
Choose from 500 different sets of 1 phase 2 metabolism flashcards on quizlet. Phase i reactions of drug metabolism involve oxidation, reduction, or hydrolysis of the parent drug, resulting in its conversion to a more polar molecule. Reactions that increase water solubility by conjugation of the drug molecule with a polar moiety such as glucuronate, acetate. Phase i and phase ii biotransformation reactions catalyzed by xenobiotic biotransforming enzymes are generally divided into two groups. 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. This renders these drugs water soluble and are easy to eliminate through the renal or biliary pathways. Cyp2c19 and cyp3a4 are the major players in the metabolism of benzodiazepines that undergo phase i metabolism figure 1. Phase i reactions involve hydrolysis, reduction and oxidation, exposing or introducing a functional group oh, nh 2, sh or cooh to increase reactivity. Drug metabolizing enzymes dmes play central roles in the metabolism, elimination and detoxification of xenobiotics and drugs introduced into the human body. Phase ii drug metabolism in skin explants 127 at aspet journals on april 17, 2020 dmd. Browse 500 sets of 1 phase 2 metabolism flashcards. Difference between phase i and phase ii metabolism compare. The below infographic represents more details on the difference. Common reactions during this phase are oxidation, reduction, and hydrolysis.
Metabolites formed in phase 2 are unlikely to be pharmacologically active. Chapters 2 and 3 deal with the chemistry of drug biotransformation, describing both phase i asynthetic and phase ii synthetic biotransformations and the enzymes that mediate them. Look at the example of a conjugation reaction in the phase 2 metabolism of aspirin. Induction of phase i, ii and iii drug metabolismtransport by xenobiotics. Much is known about their beneficial health effects, but very little is known about their metabolism.
However, phase ii metabolism remains relatively preserved in the elderly. View the rest of my pharmacology videos in order below. In phase i, enzymes such as cytochrome p450 oxidases introduce reactive or polar groups into xenobiotics. The isolation of phenol, catechol, quinol and hydroxyquinol from the ethereal sulphate fraction of the urine of rabbits receiving benzene orally. There are three possible results of phase 1 metabolism. 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 ii of metabolism may or may not be preceded by phase i reactions. This proofofconcept study investigated phase ii biotransformation of 11 test substrates in fresh fullthickness human skin explants, a model containing all skin cell types. 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 pathwaysin livermicrosomes where the drug is functionalized and phase ii pathways in liver cells where the parent or the metabolite from phase i gets conjugated. Results show that skin explants have significant capacity. Jan 06, 2019 moreover, a further difference between phase i and phase ii metabolism is that the reactions involving in phase i metabolism are oxidation, reduction and hydrolysis while the reactions involving in phase ii metabolism are methylation, glucuronidation, acetylation and sulfation. This is called conjugation and the product is called a conjugate. Pathways of biotransformation phase ii reactions springerlink.
The first phase involves oxidations, reductions or hydrolyses or a combination of any of these three, and for convenience these may be termed phase i reactions. 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. Phase i metabolism tends to be reduced in the elderly, along with polypharmacy, predisposing elderly patients to cyp450 related interactions. To address these challenges, we investigated activities of ugts. Phase 1 metabolism involves chemical reactions such as oxidation most common, reduction and hydrolysis. A comprehensive analysis of phase i and phase ii metabolism gene polymorphisms and risk of nonsmall cell lung cancer in smokers. The activity of phase ii metabolism occurs within the cytosolic region of the liver cells, containing a. 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. However, the complete pattern of benzene metabolites formed in the liver and their role in bone marrow toxicity are not fully understood. 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. Phase ii biotransformations attach a hydrophilic moiety onto drugmetabolite. The products of these chemical reactions are called metabolites. Phase i reactions involve hydrolysis, reduction and oxidation, exposing or introducing a functional group oh, nh 2. Drug metabolism can be divided into the phase i reactions functionalisation and the phase ii reactions conjugation.
Nevertheless, the fresh fullthickness skin explants represent a suitable model to study cutaneous phase ii metabolism not only in drug elimination but also in toxicity, as formation of acyl glucuronides and sulfate conjugates could play a role. Although skin is the largest organ of the human body, cutaneous drug metabolism is often overlooked, and existing experimental models are insufficiently validated. Liver microsomes are in the endoplasmic reticulum of liver cells or hepatocytes. The major site of metabolism in the body is the liver. Phase i biotransformation reactions introduce or expose functional groups on the drug with the goal of increasing the polarity of the compound. Liver phases 1 and 2 detoxification pathways what are the symptoms of a dysfunctional liver. In these conjugation reactions, drugs can be attached to any of the five polar compounds. Phase ii drug metabolism 37 apparently exhibit a broad tissue distribution, although the liver is the major site of expression for many ugts. In conclusion, there are marked differences between humans, rats and mice in the profile of major metabolites following if phase ii metabolism. The metabolism of a drug or toxin in a body is an example of a biotransformation. Phase ii metabolism involves conjugation of drugs or their metabolites with highly polar molecules. Unlike p450, phase ii reactions are concerted reactions that involve an electrophile y, a nucleophile x and a leaving group l these reactions involve a pair of electrons, i. The kidney readily eliminates the resulting watersoluble conjugate, or the bile if the molecular weight.
The terms in the table below are a collection of items from the lectures that you should be. 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. Phase i reactions include oxidation, reduction, and hydrolysis that are catalyzed by several enzymes including cytochrome p450. Pdf a comprehensive analysis of phase i and phase ii. 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. These reactions are catalysed by transferase enzymes such as glutathione stransferases. Often these reactions involve the introduction of polar functional groups such as oh to drug molecules to make them more hydrophilic. The ugt1a1, ugt1a3, ugt1a4, ugt1a6, ugt1a9, ugt2b7. 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 metabolism phase ii metabolism phenotypic variation pi boosting plavix polymorphism polytherapy portal vein product profile prothrombin time. Phase 1 andor phase 2 some drugs undergo either phase 1 or phase 2 metabolism, but most undergo phase 1. It is important to understand that these phase i and ii reactions may occur simultaneously or sequentially.
In other words, the metabolites are pharmacologically inactive. Phase i reactions convert the parent drug into more polar metabolites through introduction or exposing oh, sh, or nh2 functional groups. Introduction to phase i and ii metabolisms phase i. Phase i biotransformations include oxidation, reduction, and hydrolysis reactions.
Phase ii enzymes undoubtedly play an important role in the detoxification of various xenobiotics. Phase ii reactions many phase i metabolites are too lipophilic to be retained in the kidney tubules conjugation reactions with an endogenous substrate or an amino acid results in more water soluble compounds glucuronic acid glucuronidation sulfuric acid sulfation acetic acid acetylation. Learn vocabulary, terms, and more with flashcards, games, and other study tools. Regulation of hepatic phase ii metabolism in pregnant mice. 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.
Abnormal metabolism of fats lipids leading to abnormalities in the level of fats in the blood stream e. The body typically deals with a foreign compound by making it more watersoluble, to increase the rate of its excretion through the urine. The hepatic metabolism of benzene is thought to be a prerequisite for its bony marrow toxicity. These modified compounds are then conjugated to polar compounds in phase ii reactions. An important point to note is that some drugs dont undergo phase i metabolic reaction but instead are directly deactivated by phase ii reactions. Phase ii reactions include glucuronidation, sulfation, acetylation, methylation, conjugation with glutathione, and conjugation with amino acids such as glycine, taurine, and glutamic acid. Induction of phase i, ii and iii drug metabolismtransport by.
Although phase i drug metabolism occurs in most tissues, the primary and first pass site of metabolism occurs during hepatic circulation. Phase i and phase ii biotransformation reactions deranged. This chapter focuses on phase ii biotransformation reactions also called. Introduction to phase i and ii metabolisms phase i metabolism.
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