An example of how the understanding of stereochemistry in xenobiotic metabolism has practical applications can be seen with the nonsteroidal antiinflammatory drug ibuprofen. The key difference between phase i and phase ii metabolism is that the phase i metabolism converts a parent drug to polar active metabolites while phase ii metabolism converts a parent drug to polar inactive metabolites metabolism drug metabolism is the anabolic and catabolic breakdown of drugs by living organisms. Prebiotics are nondigestible substrates found in foods such. Clinically significant drug interactions are generally those that produce at least a 25% to 30% change in pharmacokinetic parameters. Drug metabolism is often considered during drug design. The nats identified to date and involved in human drug metabolism include nat1 and nat2. Drug metabolizing enzymes have evolved primarily as a defense against nonmedical chemicals taken up from the environment. Little overlap in substrate specificities of the two isoforms appears to exist. In the intestine for example, several drug metabolising enzymes are presumed to decrease the bioavailability of orally administered drugs or to activate environmental carcinogens. Clinical frontiers drug metabolism 2062 am j healthsyst pharmvol 59 nov 1, 2002 tional individualized therapeutics and patient care. Drug metabolizing enzymes dmes play central roles in the metabolism, elimination and detoxification of xenobiotics and drugs introduced into the human body. The liver isnt the only tissue responsible for drug metabolism.
The liver is the principal, but not the sole, site of most drug metabolism in the body. Pdf phase 1 and phase 2 drug metabolism and bile acid. Nat2 is a polymorphic enzyme, a property found to have important pharmacological consequences. Liver function and phase i drug metabolism in the elderly. There are three possible results of phase 1 metabolism. Often, phases 1 and 2 pathways work together to help in the removal of the xenobiotic. View the rest of my pharmacology videos in order be. Two general categories of drug metabolism occur in the liver. 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. 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.
Human cytochromes p450 associated with the phase 1 metabolism. Phase 1 and phase 2 drug metabolic activity of the hepargamcbals. A the accumulation of hydroxylated tolbutamide cyp2c9 activity in medium at bal culture day 14 after a 3days induction with. 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. 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. Aspirin, imipramine, desmethylimipramine, hydrocortisone, lidocaine, pentazocine, propranolol, terbutaline. Metabolism is an essential pharmacokinetic process, which renders lipid soluble and nonpolar compounds to water soluble and polar compounds so that. In part ii we will discuss the kinetics of drug metabolism and the relationship of kinetic data to the pharmacokinetics of a drug. The hydroxylated product produced from phase 1 reactions can also be conjugated by conjugation enzymes to more hydrophilic products, easier to excrete. Copyediting may lead to some differences between the fast forward version and the final version. Lipid soluble drugs are reabsorbed from the kidney and remain in the systemic circulation for longer. Path of a drug after administration by any route, a drug will reach the blood stream as.
When a p450 enzyme that is responsible for metabolizing an object drug r is inhibited by an interactant drug i then the capacity of the liver to clear the object drug from the system is decreased. Phase ii reactions include glucuronidation, sulfation, acetylation, methylation. Induction of phase i, ii and iii drug metabolismtransport. 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. Precautions drugs can interact with other drugs, foods, and beverages. Homework 1 drug metabolism 20 university of washington. In this chapter, we introduce the basics of nutrient drug interactions. 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. Induction of phase i, ii and iii drug metabolismtransport by. 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. Phase i reactions convert the parent drug into more polar metabolites through introduction or exposing oh, sh, or nh2 functional groups. The biochemical reactions are known as metabolic pathways and involve enzymes that transform one substance into another substance, either.
The cytochrome p450 enzyme system is particularly important because many different drugs also can induce or inhibit these enzymes. Liver hepatic metabolism continues to be the most important route of metabolism for foreign ingested chemicals xenobiotics and drugs. Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through. Phase i metabolism of drug candidates can be simulated in the laboratory using nonenzyme. Extrahepatic microsomal enzymes oxidation, conjugation hepatic microsomal enzymes oxidation, conjugation hepatic nonmicrosomal enzymes acetylation, sulfation,gsh. Metabolism of drugs by the kidney kidney international. Another major use was as an additive in leaded gasoline. Goller,3 dieter lang,4 jens kunze,1 bernard testa,5 ian d. 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.
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. Dissecting the reaction of phase ii metabolites of. Oct 23, 20 reduction, oxidation, hydrolysis, conjugation, glucuronidation, acetylation, sulfaction, mnemonics. Infants have almost no cyp activity, takes 1 year, at age 2 babies have the same amount of drug metabolizing enzymes as adults enzyme induction cell synthesizes an enzyme in response to a drug increased drug metabolism. The chemistry of drug metabolism uk essays ukessays. Labels with directional arrows that identify where in the body certain enzymes exist. Liver is the primary site where majority of drug metabolism occurs in two phases. Phase 1 metabolism involves chemical reactions such as oxidation most common, reduction and hydrolysis. The duration and intensity of drug action depend not only on the dose of the drug but also on the rates at which drugs are transformed to products that can be excreted readily by the kidney.
Phase i metabolism definition of phase i metabolism by. 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. This is done by adding a functional group oh here on to the drug compound. Human cytochromes p450 associated with the phase 1. Phase ii enzymes undoubtedly play an important role in the detoxification of various xenobiotics. Product areas highlighted include our portfolio of reagents for drug transport, phase i metabolism, and drug conjugate analysis. The function of metabolism is biotransform a drug to become more watersoluble and hence more excretable. Intestinal mucosa, kidney, lungs, skin and adrenals intestinal mucosa intestinal wall is rich in esterases and lipases enzymes.
Difference between phase i and phase ii metabolism. 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. 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. Phase i biotransformation reactions introduce or expose functional groups on the drug with the goal of increasing the polarity of the compound. 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.
Phase i reactions include oxidation, reduction, and hydrolysis that are catalyzed by several enzymes including cytochrome p450. This means that a constant fraction of drug is metabolized per unit of time. Prebiotics and probiotics the next issue of biofiles will explore the functionality of prebiotics and probiotics. Part 1 of the article covers the basics of drug metabolism. Bacterial flora present in the intestine and colon appear. For instance, a drug containing a benzene group may undergo phase i reactions e. Examples of drugs exhibiting first pass metabolism. 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. Cytochrome p450s and other enzymes in drug metabolism and. Drug metabolism is the term used to describe the biotransformation of.
To date, little information exists on the regulation of the nat enzymes, such. Glen,6,7 gisbert schneider1 1department of chemistry and applied biosciences, institute of pharmaceutical. Induction of drug metabolizing enzymes often leads to accelerated metabolism of multiple drugs, not just the inducing drug itself. Drug metabolisminteractions definition drug metabolism is the process by which the body breaks down and converts medication into active chemical substances. The pharmacogenetic differences in a number of phasei enzymes, such as cytochrome p450 cyp isoenzymes, dehydrogenases, and esterases, and phaseii conjugating enzymes have been extensively studied. Concluding, culturing heparg cells in the amcbal yields substantial phase 1 and phase 2 drug metabolism, while maintaining high viability, rendering dmso addition superfluous for the promotion of drug metabolism. This biotransformation can be deterred by replacing the hydrogen at the paraposition and using fluorine as a bioisostere. Therefore, amcbal culturing makes the heparg cells more suitable for testing metabolism and toxicity of drugs. That is, the rate of drug metabolism is directly proportional to the concentration of free drug, and firstorder kinetics are observed figure 1. Jianda lu, jun xue, in critical care nephrology third edition, 2019. Xenobiotic metabolism, which includes drug metabolism, has become a major pharmacolo. Induction of drugmetabolizing enzymes often leads to accelerated metabolism of multiple drugs, not just the inducing drug itself. Phase 1 and phase 2 drug metabolism and bile acid production.
Regulation of gene expression, enzyme activities, and impact of genetic variation. Cytochrome p450, drug metabolism, toxicity, reactive metabolites. There may also be differences in the quality of the graphics. Although phase i drug metabolism occurs in most tissues, the primary and first pass site of metabolism occurs during hepatic circulation. Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. The primary objective of drug metabolism is to facilitate a drugs excretion by increasing its water solubility hydrophilicity. Dmd fast forward contains papers in manuscript form that have been accepted and published in dmd but have not been copyedited and have not been assigned to an issue of the journal. The term metabolism is commonly used probably because products of drug transformation are called metabolites. In phase 2, the active drug is made inactive and transformed in such a way that it is now suitable.
Drug metabolism is the chemical alteration of a drug by the body. Phase ii of metabolism may or may not be preceded by phase i reactions. Metabolism is an essential pharmacokinetic process, which renders lipid soluble and nonpolar. Metabolism or biotransformation the conversion from one chemical form of a substance to another. In other words, the metabolites are pharmacologically inactive. Hence, drug metabolism is an important aspect of living systems.
Drug metabolism drawing of a human male showing internal organs. 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. Most of these uses have been stopped by the us epa since 1984. Interactions can lessen or magnify the desired therapeutic effect of a drug, or may cause unwanted or unexpected side effects. 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. It was also found difficult to establish an effective and safe dose for the drug 1. 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. During phase 1, the inactive drug is made active by a set of drug metabolising enzymes.
P was described as the most potent psychedelic drug in the entire 2c family with pronounced hallucinogenic effect 1. Introduction to phase i and ii metabolisms phase i. I shall discuss the subject briefly and with respect to some leading questions. These nonpathological alterations in structure andor function may affect normal physiological processes in the elderly individuals 65 years, for example drug disposition. The extent of first pass metabolism depends on the drug delivery system, the rate of dissolution, the residence time of a drug in the gastrointestinal tract, and the dose.
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 2 conjugation of a drug can occur in the absence of phase 1 metabolism. Aging is accompanied by marked changes in the physiology of many organs, as well as in their constituent cells. Learn vocabulary, terms, and more with flashcards, games, and other study tools. The contribution of these organs to drug metabolism is incompletely understood, but certainly.
875 160 111 881 402 880 703 782 509 799 468 1035 770 1347 1084 680 1228 1315 530 1225 195 1166 912 1217 1132 461 319 1346 355 251 1453 428 778 590 1122 175 1257 1026 605