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. Handbook of metabolic pathways of xenobiotics is an essential new reference which presents the metabolic fate of xenobiotics in animals and plants, and shows the metabolic pathways in the environment. Phase i biotransformation reactions introduce or expose functional groups on the drug with the goal of increasing the polarity of the compound. Effects of oral, smoked, and vaporized cannabis on endocrine pathways related to appetite and metabolism. Cocaine narcotics, temocapril angiotensinconverting enzyme inhibitors human cess mainly belong to the ces1 and ces2 family. Pharmacokinetic drug interactions occur when one drug enhances or interferes with the absorption, distribution, metabolism, or excretion of another drug resulting in a change in drug concentration in the body. Jul 01, 20 cyp is a complex and important component of drug metabolism.
Phase 1 metabolism typically subjects the drug to oxidation or hydrolysis. Learn vocabulary, terms, and more with flashcards, games, and other study tools. The liver plays a central role in metabolism of nutrients, synthesis of glucose and lipids, and detoxification of drugs and xenobiotics. Metabolism of drugs involves many pathways associated with the synthesis of endogenous substrates such as steroid hormones, cholesterol and bile acids many of the enzymes involved in drug metabolism are principally designed for the metabolism. Cyp is a complex and important component of drug metabolism. Phase i pathways in liver microsomes where the drug is functionalized and phase.
Cess are important for metabolism of ester containing drugs, and for rational drug design to increase bioavailability prodrug activation. Drug drug interactions can be categorized as pharmacokinetic or pharmacodynamic. The antituberculosis drug isoniazid induces cyp2e1, which is crucial for acetaminophen metabolism through an oxidation pathway. Drug metabolism is normally divided into two phases, phase i or functionalisation reactions and phase ii or conjugative reactions. Consider the wellknown pathway of metabolic activation of polycyclic aromatic. Cpt11, capecitabine both are anti cancer drug drug metabolism. For instance, a drug containing a benzene group may undergo phase i reactions e. Genetic variability of cyp is also a significant source of unpredictable drug effects.
Unique among drug metabolism pathways, amino acid conjugation involves initial formation of a xenobiotic acylcoa thioester that is then conjugated principally with glycine in humans. 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. The routes by which drugs may be metabolised or biotransformed are many and varied and include the chemical reactions of oxidation, reduction, hydrolysis. The biochemical processes governing drug metabolism largely determine the duration of a drugs. If youre working on or studying the effects of drug metabolisms, then this reference is for you. Nelson, lehninger principles of biochemistry, iv edition, freeman ed. 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. Metabolism describes the chemical reactions that change drugs into compounds which are easier to eliminate. The included articles support the important role of nonp450 enzymes in the clearance pathways of u. In order to avoid latestage drug failure due to factors such as undesirable metabolic instability, toxic metabolites, drug drug interactions, and polymorphic metabolism, an enormous amount of effort has been expended by both the pharmaceutical industry and academia towards developing more powerful techniques and screening assays to identify the metabolic profiles and enzymes involved in drug. Liver phases 1 and 2 detoxification pathways what are the symptoms of a dysfunctional liver.
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. The biochemical processes governing drug metabolism largely determine the duration of a drugs action, elimination, and toxicity. There are three possible results of phase 1 metabolism. Chapters 2 and 3 deal with the chemistry of drug biotransformation. Phase 1 metabolism involves chemical reactions such as oxidation most common, reduction and hydrolysis. Prodrugs are inactive drugs that undergo a chemical or biochemical conversion to the active drug. Metabolic pathways and beyond tuesday 22 january 2010 computational systems biology images from. Food and drug administrationapproved drugs over the past 10 years. Excess napqi depletes glutathione stores causing liver injury. 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. The contribution of these organs to drug metabolism is incompletely understood, but certainly. Prodrug biochemical or chemical processes drug inactive active the definition of a prodrug is controversial in some circles. Drug metabolism is often considered during drug design. It is important that these pathways are studied as the route of metabolism of a drug can determine whether it shows any pharmacological or toxicological activity.
Additional metabolites were formed by combinations of the primary metabolic pathways or by further metabolism. Phenobarbital typifies the drugs that are active when administered and then are converted to inactive and more polar metabolites in the liver. The major pathways in the liver are glucose, fatty acids. Provides a timely update to a key textbook on human drug metabolism the third edition of this comprehensive book covers basic concepts of teaching drug metabolism, starting from extreme clinical consequences to systems and mechanisms and toxicity. Coadministration of isoniazid with acetaminophen was reported to increase acetaminophen oxidation, promote gsh depletion and napqi formation and ultimately lead to increased hepatotoxicity 65,66,76.
Chief laboratory of chemical pharmacology, national heart institute, national. Current concepts provides a comprehensive understanding of the processes that take place following ingestion of a medicinal agent or xenobiotic, with an emphasis on the crucial role of metabolism biotransformation. Feb 27, 2019 drug metabolism is the term used to describe the biotransformation of pharmaceutical substances in the body so that they can be eliminated more easily. After ingestion of highly toxic doses of acetaminophen, glucuronidation and sulfation pathways get saturated and higher portion of the drug gets oxidized and excreted unchanged.
They focus on the biochemical pathways that we find in humans, and they also take into account some physiological and clinical aspects. Although phase i drug metabolism occurs in most tissues, the primary and first pass site of metabolism occurs during hepatic circulation. Metabolism and transport of acetaminophen in the liver at highly toxic doses. Request pdf pathways of drug metabolism this chapter discusses pathways of drug metabolism.
Drug metabolites can have the same, increased or decreased activity compared to parent compound. The notes, and the corresponding slides, are also freely available in pdf and powerpoint formats. Biotransformation of drug candidates by noncyp metabolic. Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. It provides an invaluable introduction to the core areas of pharmacology and examines recent progress and advances in this fast moving field and its. The biochemical processes governing drug metabolism largely determine the duration of a drug s action, elimination, and toxicity. The kidney readily eliminates the resulting watersoluble conjugate, or the bile if the molecular weight exceeds 300. 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.
Effects of oral, smoked, and vaporized cannabis on endocrine. The end product of a pathway may be used immediately, initiate another metabolic pathway or be stored for later use. 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. This biotransformation can be deterred by replacing the hydrogen at the paraposition and using fluorine as a bioisostere. Presenting a comprehensive guide to understanding the metabolisms of xenobiotics, the. 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. Markey laboratory of neurotoxicology nimh, nih dec. Drug metabolism is an immense area of study and this is reflected in the range of chemical reactions the substrates can undergo during metabolism, e.
This chapter discusses pathways of drug metabolism. 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. It is the root of many drug interactions due to inhibition, induction, and competition for common enzymatic pathways by different drugs. Metabolism or biotransformation it is the enzymatic conversion from one chemical form of a substance to another. The drug metabolism process occurring in organs other than the. Metabolism occurred via three major pathways hydroxylation of the phenyl m35, opening of the piperidine m25 and m34, and epoxidation of the ethylene on the acryloyl moiety with further hydrolysis to dihydrodiol pci45227, and m37. This article is based on the first of two university of london special university lectures in pharmacology on biochemical and clinical implications of studies in drug metabolism, given at guys hospital medical school, may 17, 1954. They are therefore expressed also at other interfaces of the body with the environment such as the skin, lungs, and the kidney. Special section on emerging novel enzyme pathways in drug. The primary objective of drug metabolism is to facilitate a drug s excretion by increasing its water solubility hydrophilicity. In other words, the metabolites are pharmacologically inactive. In this chapter, you will learn about the pathways that are involved in the metabolism of carbohydrates, proteins, and fats. Sarita sharma assistant professor of pharmacology mumbai 2.
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