The liver is the principal, but not the sole, site of most drug metabolism in the body. Ontogeny of phase i metabolism of drugs allegaert 2019 the. If it stays longer then it can start acting in other unnecessary places in the body giving rise to what we commonly refer to as sideeffects. They are therefore expressed also at other interfaces of the body with the environment such as the skin, lungs, and the kidney.
Phase i metabolism consists of reduction, oxidation, or hydrolysis reactions. All drugs are subject to metabolic process, in general these process serve to increase the polarity of molecules in an effort to increase excretion. Prebiotics are nondigestible substrates found in foods such. Drug metabolism usually occurs in the liver, but occasionally can take place in the gastrointestinal tract, lungs, kidneys, skin or plasma.
Whilst the impact of metabolism on the drug duration of action is major concern, a knowledge of the metabolic routes can be. The diester prodrugs were of special interest, since they combine an enhanced bioavailability and. Phase 1 and phase 2 drug metabolism and bile acid production. Phase i reactions convert the parent drug into more polar metabolites through introduction or exposing oh, sh, or nh2 functional groups. The process effectively eliminates the parent drug. Homework 1 drug metabolism 20 university of washington. Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems.
Metabolism is an essential pharmacokinetic process, which renders lipid soluble and nonpolar compounds to water soluble and. An example of how the understanding of stereochemistry in xenobiotic metabolism has practical applications can be seen with the nonsteroidal antiinflammatory drug ibuprofen. 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. The human liver cell line heparg has been recognized as a promising source for in vitro testing of metabolism and toxicity of compounds. However, they do destabilize and unmask or expose a functional group. In part ii we will discuss the kinetics of drug metabolism and the relationship of kinetic data to the pharmacokinetics of a drug. Phase i metabolism involves functionalization reactions. 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. Glen,6,7 gisbert schneider1 1department of chemistry and applied biosciences, institute of pharmaceutical. Jianda lu, jun xue, in critical care nephrology third edition, 2019. The process of metabolism is divided into 3 phases. P450 oxidoreductase, p450 reductase, por, cpr, cypor, is a membranebound enzyme required for electron transfer to cytochrome p450 in the microsome of the.
Two phases in metabolism are classically recognized. Clinical pharmacokinetics pharmacology education project. 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. Phase ii of metabolism may or may not be preceded by phase i reactions. Human cytochromes p450 associated with the phase 1. In phase 2, the active drug is made inactive and transformed in such a way that it is now suitable. However, phase ii metabolism remains relatively preserved in the elderly. The primary site of drug metabolism is the liver, the organ that plays a major role in metabolism, digestion, detoxification, and elimination of substances from the body. Induction of phase i, ii and iii drug metabolismtransport by. Phase i reactions involve hydrolysis, reduction and oxidation, exposing or introducing a functional group oh, nh 2, sh or cooh to increase reactivity and slightly increase hydrophilicity. 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. 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 i and phase ii reactions of drug authorstream. Major location of drug metabolizing enzymes dysfunction can lead to impaired drug metabolismdecreased enzyme activity first pass metabolism effected may inc 24 x bioavailiability results in exaggerated pharmacological responses and adverse effects.
Phase 1 metabolism involves chemical reactions such as oxidation most. The chemistry of drug metabolism uk essays ukessays. The participation of phase ii drug metabolizing enzymes in the metabolism of clinically used drugs is shown in fig. Drug metabolizing enzymes dmes play central roles in the metabolism, elimination and detoxification of xenobiotics and drugs introduced into the human body. In spite of the lack of data on 2cp metabolism, reasonable predictions could be made. 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. Phase i biotransformation reactions introduce or expose functional groups on the drug with the goal of increasing the polarity of the compound. The term metabolism is commonly used probably because products of drug transformation are called metabolites. Conjugation reactions in which a polar molecule is linked to a suitable functional group on a drug or one of its phase 1 metabolites.
In other words, the metabolites are pharmacologically inactive. Phase 1 metabolism involves chemical reactions such as oxidation most common, reduction and hydrolysis. However, currently the hepatic differentiation of these cells relies on exposure to dimethylsulfoxide dmso, which, as a side effect, has a cytotoxic effect and represses an allround hepatic functionality. It was also found difficult to establish an effective and safe dose for the drug 1. Drug metabolisminteractions definition drug metabolism is the process by which the body breaks down and converts medication into active chemical substances. Since the introduction of the electrospray ionization esi and atmospheric pressure chemical ionization apci techniques, lcms has become an ideal and widely used method in the identification, structure characterization and quantitative analysis of drug metabolites owing to its superior specificity, sensitivity and efficiency over others such as. These reactions serve to convert lipophilic drugs into more polar. Phase i metabolism definition of phase i metabolism by. The primary objective of drug metabolism is to facilitate a drug s excretion by increasing its water solubility hydrophilicity.
Liver hepatic metabolism continues to be the most important route of metabolism for foreign ingested chemicals xenobiotics and drugs. The primary objective of drug metabolism is to facilitate a drugs excretion by increasing its water solubility hydrophilicity. View the rest of my pharmacology videos in order be. Phase 1 drug metabolism flashcards in university pharmacy. Pdf while the mammalian eye is seldom considered an organ of drug. Drug metabolizing enzymes thermo fisher scientific. Phase ii reactions include glucuronidation, sulfation, acetylation, methylation. Conjugation reactions in which a polar molecule is linked to a suitable functional group on a drug or one of its phase 1 metabolites types of phase 2 metabolism reactions 1. Drug metabolism made easy using kings college london. As explained in great detail in other chapters see 5.
Biochemistry, biotransformation statpearls ncbi bookshelf. The cytochrome p450 enzyme system is particularly important because many different drugs also can induce or inhibit these enzymes, resulting in changing. Transformation of drug into a more polar metabolite by introducing or unmasking a functional group e. Metabolism is an essential pharmacokinetic process, which renders lipid soluble and nonpolar compounds to water soluble and polar compounds so that. Goller,3 dieter lang,4 jens kunze,1 bernard testa,5 ian d. 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. The biochemical reactions are known as metabolic pathways and involve enzymes that transform one substance into another substance, either. Characterization of phase i and glucuronide phase ii. Product areas highlighted include our portfolio of reagents for drug transport, phase i metabolism, and drug conjugate analysis. Gsts are a group of phase ii drugmetabolizing enzymes that catalyze the binding of. Precautions drugs can interact with other drugs, foods, and beverages. Path of a drug after administration by any route, a drug will reach the blood stream as.
P450 oxidoreductase, p450 reductase, por, cpr, cypor, is a membranebound enzyme required for. Petra jancovaa, pavel anzenbacherb eva anzenbacherova. 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. Introduction to phase i and ii metabolisms phase i. 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. The contribution of these organs to drug metabolism is incompletely understood, but certainly. The exposed functional group allows for the attachment of water soluble. Drug metabolism is an immense area of study where drugs undergo a range of enzymemediated chemical reactions, such as oxidation, reduction, hydrolysis, hydration, conjugation, and migration. Extrahepatic microsomal enzymes oxidation, conjugation hepatic microsomal enzymes oxidation, conjugation hepatic nonmicrosomal enzymes acetylation, sulfation,gsh. Induction of phase i, ii and iii drug metabolismtransport. The metabolism phase is absent for the few drugs that are not transformed. Benzodiazepines are one of the most commonly prescribed medications to treat anxiety, insomnia, and other conditions in the united states. Drug metabolism is the chemical alteration of a drug by the body.
This is done by adding a functional group oh here on to the drug compound. This chapter introduces xenobiotic metabolism in this chapter, the terms xenobiotic metabolism and xenobioticmetabolizing enzyme will be used in preference to drug metabolism and drugmetabolizing enzyme because most of the enzymes involved recognize various substrates including drugs, industrial chemicals and. Phase ii drug metabolism is a conjugation reaction. Another major use was as an additive in leaded gasoline. Enzymes in the liver are responsible for chemically changing drug components into substances known as metabolites. Drug metabolizing enzymes have evolved primarily as a defense against nonmedical chemicals taken up from the environment. Drug metabolism drawing of a human male showing internal organs. L1 showed higher gr activity after 1 day exposure, although after 4 days of exposure the gr decreased in the oysters exposed to 1 and 100. Oct 23, 20 reduction, oxidation, hydrolysis, conjugation, glucuronidation, acetylation, sulfaction, mnemonics. Most of these uses have been stopped by the us epa since 1984.
Although glucuronidation generally is classified as phase ii metabolism the phase occur. There are three possible results of phase 1 metabolism. It is highly variable among drugs and depends on biological conditions. P was described as the most potent psychedelic drug in the entire 2c family with pronounced hallucinogenic effect 1. Oxidation is much the commonest form of phase 1 reaction and involves chiefly members of the. Although phase i drug metabolism occurs in most tissues, the primary and first pass site of metabolism occurs during hepatic circulation. Liver is the primary site where majority of drug metabolism occurs in two phases. Metabolism or biotransformation the conversion from one chemical form of a substance to another. The purpose of a phase 1 drug test is to evaluate the safety of a drug, figure out its ideal dosage range, and identify possible side effects from taking it. Phase ii enzymes undoubtedly play an important role in the detoxification of various xenobiotics. Pdf phase i and phase ii ocular metabolic activities and the role. The conduct of drug metabolism studies considered good. Intestinal mucosa, kidney, lungs, skin and adrenals intestinal mucosa intestinal wall is rich in esterases and lipases enzymes.
Interactions can lessen or magnify the desired therapeutic effect of a drug, or may cause unwanted or unexpected side effects. Metabolism simply means conversion of a compound drug from one form into another by enzymes in the body. Phase i in which drug molecules are altered chemically by oxidation, reduction or hydrolysis to make them suitable for phase ii reactions or for excretion. Major location of drug metabolizing enzymes dysfunction can lead to impaired drug metabolismdecreased enzyme activity first pass metabolism effected may inc 24 x bioavailiability results in exaggerated pharmacological responses and adverse effects cardiac failure causes decreased blood flow to the liver. Predicting metabolism cambridge medchem consulting.
Phase i and phase ii reactions of drug authorstream presentation. Phase i metabolism tends to be reduced in the elderly, along with polypharmacy, predisposing elderly patients to cyp450 related interactions. 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. During phase 1, the inactive drug is made active by a set of drug metabolising enzymes. The hydroxylated product produced from phase 1 reactions can also be conjugated by conjugation enzymes to more hydrophilic products, easier to excrete. 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 elimination. Drug metabolism in the liver request pdf researchgate. Cyp2c19 and cyp3a4 are the major players in the metabolism of benzodiazepines that undergo phase i metabolism figure 1. Labels with directional arrows that identify where in the body certain enzymes exist. Current trends in drug metabolism and pharmacokinetics. 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 reactions include oxidation, reduction, and hydrolysis that are catalyzed by several enzymes including cytochrome p450. The scheme of typical glucuronidation reactions is shown in figure 1.
Prebiotics and probiotics the next issue of biofiles will explore the functionality of prebiotics and probiotics. 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 ii biotransform of drugs linkedin slideshare. The detection and quantification of lorazepam and its 3oglucuronide conjugate in fingerprint deposits by lcmsms.
The medicine must remain active in the body only for a certain period of time. Human cytochromes p450 associated with the phase 1 metabolism. Capturing ontogeny of enzymes involved in phase i metabolism is. Bacterial flora present in the intestine and colon appear. Drug metabolism part1 objectives to understand the following basic principles with regard to drug metabolism.
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