Phase 1 and phase 2 reactions in drug metabolism pdf

Role of metabolism in pediatric and elderly new born has low g. In phase i, enzymes such as cytochrome p450 oxidases introduce reactive or polar groups into xenobiotics. The enzymecatalyzed reactions of phase i metabolism bind oxygen, hydrogen, water, or amino acids to the lipophilic drug molecule to expose or introduce a hydroxyl oh, amino nh 2, sulfhydryl sh, or carboxyl cooh polar functional group, and thus, result in a modest increase in the parent drugs water solubility. Fast mimicking of phase 1 and 2 metabolism of acetaminophen using the roxy ec system fast mimicking of phase 1 and 2 metabolism of acetaminophen using the roxy ec system fast mimicking of phase 1 and 2 metabolism of acetaminophen using the roxy ec system figure 1. Often these reactions involve the introduction of polar functional groups such as oh to drug molecules to make them more hydrophilic. Phase i metabolism converts the drug into metabolite by formation of a new functional group or modifying it, while phase ii metabolism or reactions involve conjugation with indigenous substance. However, the compound itself has no pharmacological activity. During these reactions, certain groups are added so that the drug can undergo the second phase to produce conjugation products.

Phase i reactions, and the conjugation reactions are called phase ii reactions table a. Often, phases 1 and 2 pathways work together to help in the removal of the xenobiotic. Phase ii reactions involve conjugation by coupling the drug or its metabolites to another molecule, such as glucuronidation, acylation, sulfate, or glicine. Despite these and other shortcomings 91, the traditional classification in phase 1 and 2 reactions remains helpful to structure the wide range of. Phase 1 reactions phase 1 reactions are classified into oxidation, reduction and hydrolysis. Phase 1 drug metabolism functional conversion to polar metabolites in. In addition to the liver, every biological tissue of the body has the ability to metabolize drugs. Abnormal metabolism of fats lipids leading to abnormalities in the level of fats in the blood stream e. The drug metabolism process occurring in organs other than the figure 1. Examples of phase i drug substrates are listed in table 41. Phase i and phase ii biotransformation reactions catalyzed by xenobiotic biotransforming enzymes are generally divided into two groups.

Phase ii reactions include glucuronidation, sulfation, acetylation, methylation. This chapter answers parts from section biv of the 2017 cicm primary syllabus, which expects the exam candidate to describe the mechanisms of drug clearance and metabolism. Phase 2 drug metabolism enzymatic conjugation reaction in the intestine and liver. Phase 2 metabolism involves reactions that chemically change the drug or phase 1 metabolites into compounds that are soluble enough to be excreted in urine. The actual activity of a drug can be altered in one of 3 ways by phase 1 metabolism. 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. 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. This chapter focuses on phase ii biotransformation reactions also called. Phase i reactions of drug metabolism involve oxidation, reduction, or hydrolysis of the parent drug, resulting in its conversion to a more polar molecule. Phase 2 conjugation of a drug can occur in the absence of phase 1 metabolism. 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.

Safety considerations in phase 1 trials joseph toerner, md, mph deputy director for safety. We know that elimination of apap involves phase i, ii, and iii metabolism. Phase i biotransformation reactions are simple reactions compared to phase ii reactions. Phase i reactions include oxidation especially by the cytochrome p450 group of enzymes, also called mixedfunction oxidases, reduction, deamination, and hydrolysis. Phase i reactions include oxidation, reduction, and hydrolysis that are catalyzed by several enzymes including cytochrome p450. Explore drug metabolism and drug interactions types of phase 1 trials. For example, phase i metabolism converts acetonitrile to hoch2cn, which. These modified compounds are then conjugated to polar compounds in phase ii reactions. Phase ii metabolism removes most of the drug prior to phase i and involves ugt1a1 and 1a6, as well as sult1a1, 1a34, and possibly 1e1. As drug concentration increases, metabolism shifts from firstorder to zeroorder kinetics. Collectively, the results of this study suggest that the olfactory rosettes are important sites of extrahepatic biotransformation in coho salmon, and that tissue specificdifferences in phase i metabolism may lead to contrasting tissuespecific biotransformation capabilities in coho salmon. Phase i reactions phase i reactions also termed nonsynthetic reactions may occur by oxidation, reduction, hydrolysis, cyclization, and decyclization addition of oxygen or removal of hydrogen, carried out by mixed function oxidases, often in the liver. 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 reactions convert the parent drug into more polar metabolites through introduction or exposing oh, sh, or nh2 functional groups.

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. Learn vocabulary, terms, and more with flashcards, games, and other study tools. In phase i reactions, a small polar group containing both positive and negative charges is either exposed on the toxicant or added to the toxicant. Despite these and other shortcomings 91, the traditional classification in phase 1 and 2 reactions remains helpful to structure the wide range of reactions and this classification is used below to guide the reader through the metabolism of endogenous steroids. These reactions include hydrolysis, reduction, and oxidation. Phase i biotransformation reactions introduce or expose functional groups on the drug with the goal of increasing the polarity of the compound. 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 enzymes are found in high concentrations in the smooth endoplasmic reticulum of the liver. Figure 2 warfarin is used as an anti pharmacologically active and they are excreted by the kidney. Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through.

The metabolism phase is absent for the few drugs that are not transformed. An important point to note is that some drugs dont undergo phase i metabolic reaction but instead are directly deactivated by phase ii reactions. Drug metabolism is normally divided into two phases, phase i or functionalisation reactions and phase ii or conjugative reactions. Hypersensitivity reactions product development halted. Phase i metabolism is predominantly mediated by cyp2e1 and produces a reactive metabolite. As explained in great detail in other chapters see 5. These reactions are catalysed by transferase enzymes such as glutathione stransferases. Biochemical and molecular principles of drug action biochemical and molecular principles of drug action. If the metabolites of phase i reactions are sufficiently polar, they may be readily excreted at this point.

It is convenient to divide drug metabolism into two phases i and ii which sometimes. Recently, a third phase of metabolism has been proposed phase iii, in recognition of the role of membrane transporters on the biliary excretion of drugs and their metabolites, as well as the ef. Sult1 and 2 are most important in the metabolism of drugs. Specifically, this chapter exists because in question 20 from the first paper of 2016 the official college answer chided the candidates for not knowing enough about phase i and phase ii reactions. Phase i biotransformations include oxidation, reduction, and hydrolysis reactions. Metabolism occurs in two phases, phase i metabolism, and phase ii metabolism.

Although phase i drug metabolism occurs in most tissues, the primary and first pass site of metabolism occurs during hepatic circulation. It is highly variable among drugs and depends on biological conditions. Overview definition consequences types phase iii in detail. The metabolism of a drug or toxin in a body is an example of a biotransformation. In this case, if 500 mg is present in the body at time zero, after metabolism, 450 mg may be present at 1 hour and 400 mg at 2 hours illustrating a maximal clearance of 50 mgh and no specific halflife. Introduction to phase i and ii metabolisms phase i. In these reactions, the molecule oh o o ch 3 figure 2 warfarin is used as an antipharmacologically active and they are excreted by the kidney. Adds hydrophilic groups to handles created in phase i metabolism. The drug metabolism happening in the liver is termed as hepatic metabolism. The hydroxylated product produced from phase 1 reactions can also be conjugated by conjugation enzymes to more hydrophilic products, easier to excrete. Drug metabolism is the phase of biochemical transformation of the drug.