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. This is an advanced course, intended to present and discuss drug metabolism of the major drugs of abuse and its importance in the interpretation of drug test results in the clinical laboratory. 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. The products of these chemical reactions are called metabolites. Handbook of drug metabolism paul gerard pearson, larry c. Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. Phase i reactions include oxidation, reduction, and hydrolysis that are catalyzed by several enzymes including cytochrome p450. Within the body, the liver is the primary organ responsible for metabolizing i. It was established in 2000 and is published 10 times per year by bentham science publishers. The resulting product is too polar to recross membranes back into tissues and is readily excreted.
Phase ii of metabolism may or may not be preceded by phase i reactions. 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. For instance, a drug containing a benzene group may undergo phase i reactions e. Drug metabolism made easy using kings college london. Although we ordinarily think of drug metabolism as a process that inactivates drugs, that is not always the case. Though they may not be involved in the metabolism of a broad range or significant number of drugs, if they are the primary enzyme responsible for. In the study of absorption, distribution, metabolism and elimination adme, humans or animals are administered a mixture of known amount of a drug labeled and nonlabeled for the metabolism experiments to evaluate the mass balance and tissue distribution of the drug 5, 6. In this chapter, we introduce the basics of nutrientdrug interactions. Cytochrome p450s and other enzymes in drug metabolism and. Glen,6,7 gisbert schneider1 1department of chemistry and applied biosciences, institute of pharmaceutical sciences, eth zurich, 8093 zurich, switzerland. Cytochrome p450 cyp and its central role in drug metabolism, drugdrug interactions and pharmacogenetics will be discussed. 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. Its a presentation done by me in the given topic at the pharmacology seminar organised at r.
Jianda lu, jun xue, in critical care nephrology third edition, 2019. 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. Transformation of drug into a more polar metabolite by introducing or unmasking a functional group e. In other words, the metabolites are pharmacologically inactive.
The primary objective of drug metabolism is to facilitate a drugs excretion by increasing its water solubility hydrophilicity. Drug metabolism as a discipline plays an important role in drug discovery and development and the effects of drug metabolism on pharmacokinetics pk, pharmacodynamics pd, and safety should be. Phase i functionalisation reactions phase ii conjugation reactions isomerisation e. A drug may inhibit one isoenzyme while being itself a substrate of another isoenzyme e. In part ii we will discuss the kinetics of drug metabolism and the relationship of kinetic data to the pharmacokinetics of a drug.
In the development of any new drug, it is highly likely that drug metabolism will play. There are three possible results of phase 1 metabolism. Drug metabolizing enzymes dmes play central roles in the metabolism, elimination and detoxification of xenobiotics and drugs introduced into the human body. Computational models of drug metabolism prediction have focused mainly on cytochrome p450 enzymes, because drugdrug interactions. The vast majority of phase i reactions are catalyzed by the cytochrome p450 superfamily of hemoproteins. Pathways of drug metabolism drug metabolism is divided into. Drug metabolism is the chemical alteration of a drug by the body. Prebiotics are nondigestible substrates found in foods such.
Product areas highlighted include our portfolio of reagents for drug transport, phase i metabolism, and drug conjugate analysis. They are therefore expressed also at other interfaces of the body with the environment such as the skin, lungs, and the kidney. Excretion of drug or metabolites can help eliminate drug from the bloodstream. Phase i biotransformation reactions introduce or expose functional groups on the drug with the goal of increasing the polarity of the compound. Metabolism simply means conversion of a compound drug from one form into another by enzymes in the body. Topics include the effects of phase i and phase ii metabolic reactions, the bodys elimination of drugs and drug metabolites, and the various factors. Phase i and phase ii reactions of drug authorstream presentation. Within it, the proteins known as the cytochrome p450s have the primary role, and so snps in the genes encoding this family of proteins play a major role in drug metabolism. Cytochromes cyp p450 are a superfamily of proteins involved mainly in metabolism of xenobiotics i. Induction of phase i, ii and iii drug metabolismtransport. P450 oxidoreductase, p450 reductase, por, cpr, cypor, is a membranebound enzyme required for electron transfer to cytochrome p450 in the microsome of the. Drug metabolism oxidation humans have 18 families of cytochrome p450 genes and 43 subfamilies. Drugs get metabolize through various types of metabplic reactions, in this video, there is explanation about these reactions with examples.
In vitro drug metabolism using liver microsomes knights. Changes in diet may lead to significant alterations in drug metabolism 18, 19. The journal will accept original submissions in english on the understanding that the work is unpublished and is not being considered for publication. 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. Introduction to phase i and ii metabolisms phase i. The biochemistry of drug metabolism an introduction kramer. Drug metabolism and pharmacokinetics journal elsevier. Cytochrome p450 cytochrome p450 cyp enzymes are the most important in biotransformation in terms of the catalytic versatility and number of xenobiotics that it metabolizes. In addition to the liver, every biological tissue of the body has the ability to metabolize drugs. Path of a drug after administration by any route, a drug will reach the blood stream as schematically shown in f2. The remaining cyp isoforms involved in human drug metabolism are present in the liver in varying amounts, and each is thought to contribute 23% or less of the cypmediated drug oxidation reactions. Drug metabolism drugs merck manuals consumer version.
The contribution of these organs to drug metabolism is incompletely understood, but certainly. Drug metabolism free download as powerpoint presentation. These reactions are categorized as phase i and phase ii. The human cyp3a family is clinically very important because it has been shown to catalyze the metabolism of an amazingly large.
Drugmetabolizing enzymes and transporters present in extrahepatic tissues, such as nasal mucosa and the respiratory tract, have been particularly discussed. 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. Metabolism is an essential pharmacokinetic process, which renders lipid soluble and nonpolar compounds to water soluble and polar compounds so that. Conjugation reactions phase ii biotransformations attach a hydrophilic moiety onto drugmetabolite. Extrahepatic microsomal enzymes oxidation, conjugation hepatic microsomal enzymes oxidation, conjugation hepatic nonmicrosomal enzymes acetylation, sulfation,gsh. Drug metabolism drug metabolism medical treatments. Goller,3 dieter lang,4 jens kunze,1 bernard testa,5 ian d.
The journals scope covers all the basic and applied research in drug delivery and targeting at molecular and cellular levels and novel delivery systems. 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 reactions are catalysed by enzymes and happen mostly in the liver, though some changes take place in the gut wall. Phase ii enzymes undoubtedly play an important role in the detoxification of various xenobiotics. 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. In the intestine for example, several drug metabolising enzymes are presumed to decrease the bioavailability of orally administered drugs or to activate environmental carcinogens. In fact, biotransformation can have four possible outcomes.
Part 1 of the article covers the basics of drug metabolism. Path of a drug after administration by any route, a drug will reach the blood stream as. Phase i metabolism definition of phase i metabolism by. Cytochrome p450 isozyme system play important role in phase i. Further, characterization of the enzymes responsible for metabolism reaction phenotyping allows prediction, at least at the qualitative level, of factors including metabolic drug. In phase ii more lipophilic groups are conjugated to the. Unless the concentration of the alternative substrate e. Some drugs are chemically altered by the body metabolized. As marketed antiallergic drugs include both racemates and enantiomers, aspects of stereoselective absorption, distribution, metabolism, and excretion have been discussed. The term metabolism is commonly used probably because products of drug transformation are called metabolites. In this chapter, we introduce the basics of nutrient drug interactions. The cytochrome p450 enzyme system is particularly important because many different drugs also can induce or inhibit these enzymes.
Drug metabolizing enzymes have evolved primarily as a defense against nonmedical chemicals taken up from the environment. Learn vocabulary, terms, and more with flashcards, games, and other study tools. Metabolism is an essential pharmacokinetic process, which renders lipid soluble and nonpolar. For example, rifampicin, an antibiotic used in tuberculosis, or phenytoin and phenobarbital, which are used as antiepileptic agents, all induce accelerated inactivation of each other and of contraceptive agents. 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. 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. Oct 23, 20 reduction, oxidation, hydrolysis, conjugation, glucuronidation, acetylation, sulfaction, mnemonics.
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 convert the parent drug into more polar metabolites through introduction or exposing oh, sh, or nh2 functional groups. Early studies of drug metabolism demonstrated the nadphdependent oxidation of various compounds by liver microsomes 4,5, and the enzyme responsible for this oxidation was later described as an ironcontaining molecule having an absorbance peak of 450 nm, hence. The substances that result from metabolism metabolites may be inactive, or they may be similar to or different from. Drug metabolism and pharmacokinetics dmpk is an official online journal of the japanese society for the study of xenobiotics jssx, and it replaces the jssxs former journal, xenobiotic metabolism and disposition. Induction of drug metabolizing enzymes often leads to accelerated metabolism of multiple drugs, not just the inducing drug itself. This biotransformation can be deterred by replacing the hydrogen at the paraposition and using fluorine as a bioisostere.
Phase ii biotransform of drugs linkedin slideshare. Drug metabolism drawing of a human male showing internal organs. The total dose used in the radiolabel studies is usually a. Phase 1 metabolism involves chemical reactions such as oxidation most common, reduction and hydrolysis. Reduction nadphcytochrome p450 reductase cytochrome p450 reductase also known as nadph. Labels with directional arrows that identify where in the body certain enzymes exist. Induction of phase i, ii and iii drug metabolismtransport by. Drug metabolism university of california, san diego. 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.
Major location of drug metabolizing enzymes dysfunction can lead to impaired drug metabolism decreased 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. Chapters 2 and 3 deal with the chemistry of drug biotransformation. Cyp1 drug metabolism 3 subfamilies, 3 genes, 1 pseudogene cyp2 drug and steroid metabolism subfamilies, 16 genes, 16 pseudogenes cyp3 drug metabolism 1 subfamily, 4 genes, 2 pseudogenes. Drug metabolism usually occurs in the liver, but occasionally can take place in the gastrointestinal tract, lungs, kidneys, skin or plasma.
View the rest of my pharmacology videos in order be. Insufficient studies have been conducted either in young or elderly volunteers to determine in a consistent manner the effects of diet and food on drug metabolism. Many drugdrug interactions occur because of altered metabolism inhibition of metabolism the efficacy of the drug may be decreased i. The conduct of drug metabolism studies considered good. According to the journal citation reports, the journal has a 2014 impact factor of 2.
Because of the considerable variability in metabolism among different species it is essential and valuable early in drug discovery to use in vitro systems with humanderived material, since man is generally the target species. The liver is the principal, but not the sole, site of most drug metabolism in the body. Drug metabolism part1 objectives to understand the following basic principles with regard to drug metabolism. Prebiotics and probiotics the next issue of biofiles will explore the functionality of prebiotics and probiotics.
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. Clinically relevant genetic variations in drug metabolizing. Pdf drug metabolism in drug discovery and development. Two phases in metabolism are classically recognized. Pathways of drug metabolism drug metabolism is divided into two phases.
Overview it is important to identify the enzymes that significantly contribute to the metabolism of a drug candidate and to evaluate the potential of a drug candidate to be a victim drug a drug which is cleared by a single route of elimination or a perpetrator a factor or drug which alters. This can cause drug interactions with other drugs metabolized by p450 isozymes that will continue for several weeks after administration of prozac is discontinued. The cytochrome p450 p450 enzymes are the major cata lysts involved in the metabolism of drugs. Phase i and phase ii reactions of drug authorstream. Pharmacogenetics of drugmetabolizing enzymes in us hispanics. The medicine must remain active in the body only for a certain period of time. Drug metabolism is often considered during drug design. Firstpass effect the reduction in oral bioavailability due to metabolism in the gi andor liver. Enzymes in the liver are responsible for chemically changing drug components into substances known as metabolites. The editorinchief is michael sinz bristolmyers squibb.
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