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II. Where does metabolism occur in the body? The liver is the primary site for metabolism. Liver contains the necessary enzymes for metabolism of drugs and other xenobiotics. These enzymes induce two metabolism pathways: Phase I (functionalization reactions) and Phase II (biosynthetic reactions) metabolism. Some typical examples of Phase I metabolism include oxidation and hydrolysis. The enzymes involved in Phase I reactions are primarily located in the endoplasmic reticulum of the liver cell, they are called microsomal enzymes. Phase II metabolism involves the introduction of a hydrophilic endogenous species, such as glucuronic acid or sulfate, to the drug molecule. Enzymes involved in phase II reactions are mainly located in the cytosol, except glucuronidation enzyme, which is also a microsomal enzyme. Drugs are usually lipophilic substances (Oil-like) so they can pass plasma membranes and reach the site of action. Drug metabolism is basically a process that introduces hydrophilic functionailities onto the drug molecule to facilitate excretion. When the drug molecule is oxidized, hydrolyzed, or covalently attached to a hydrophilic species, the whole molecule becomes more hydrophilic, and is excreted more easily. Drugs often undergo both Phase I and II reactions before excretion. The Phase I reaction introduces a functional group such as a hydroxyl group onto the molecule, or exposes a preexisting functional group, and Phase II reaction connects this functional group to the endogenous species such as a glucuronic acid. The modified drug molecule may then be hydrophilic enough to be excreted. Although liver is the primary site for metabolism, virtually all tissue cells have some metabolic activities. Other organs having significant metabolic activities include the gastrointestinal tract, kidneys, and lungs. When a drug is administrated orally, it undergoes metabolism in the GI track and the liver before reaching systemic circulation. This process is called first-pass metabolism. First-pass metabolism limits the oral bioavailability of drugs, sometimes significantly. Why are drugs metabolized? Small molecule drugs are xenobiotics, foreign molecules, that the human body attempts to deal with through a number of responses. Some drugs are excreted from the human body intact. Most drugs, however, need to be modified structurally to facilitate excretion. These modification processes are called drug metabolism. Drug metabolism is a detoxification function the human body possesses to defend itself from environment hostility. When a person is sick, however, the body needs some kind of medication to fight the disease. Ideally, a drug should reach the site of action intact, cure the disease, and leave the body after it completes its mission. However, drug developers often face the dilemma that a potential drug is either metabolized/excreted from the body too fast, that the drug can not reach its therapeutic effect, or too slow, that it stays in the body for a long time, causing side effects. (Remember the drug is a xenobiotic that the normal human body doesn't need.) The study of drug metabolism, therefore, serves primarily two purposes: to elucidate the function and fate of the drug, and to manipulate the metabolic process of a potential drug. III. What happens to drugs once they are metabolized? Drugs are ultimately excreted from the body through various routes. The kidney is the major organ for drug excretion. It excretes hydrophilic drug and drug metabolites through glomerular filtration. Macromolecules such as proteins are retained. Lipophilic drug molecules are not directly excreted from the kidney. Only after they are metabolized into more hydrophilic molecules, can they be excreted through the kidneys into the urine. Drugs and their metabolites are also excreted into bile. This is usually mediated by protein transporters. Drugs and their metabolites in bile are eventually released into the intestinal tract. The drugs may be reabsorbed into the body from the intestine. Drug metabolites such as glucuronide conjugates, may be converted back to the parent drug in the intestine through glucuronidase enzyme, and then reabsorbed into systemic circulation. This drug recycling process is called enterohepatic recycling. This process, if extensive, may prolong the half-life of the drug. The bile drugs and drug metabolites, if not reabsorbed by intestine, are excreted from the body through feces. Also, a variety of orally administrated drugs are excreted through feces because they are not absorbed through the intestine. Oral bioavailability constitutes a major challenge for drug developers. Other routes of excretion, such as sweat, tears, and saliva, are quantitatively less important. Excretion through breast milk is not important to the mother, but may be of key importance to the baby, because the drug may be toxic to the baby. Pulmonary excretion is important for anesthetic gases and vapor drugs. IV. Are there common motifs (consensus sites) on molecules where metabolism occurs? As is pointed out, small molecule drugs are usually lipophilic substances that can penetrate cell membranes to reach the site of action, and drug metabolism is a process of introducing hydrophilic functional groups onto the drug molecule. The most common phase I reactions are oxidative processes that involve cytochrome P450 enzymes. These enzymes are a super family of proteins found in all living organisms. These enzymes catalyze the following reactions: aromatic hydroxylation; aliphatic hydroxylation; N-, O-, and Sdealkylation; N-hydroxylation; N-oxidation; sulfoxidation; deamination; and dehalogenation. These enzymes are also involved in a number of reductive reactions, generally under oxygen-deficiency condition. Hydrolysis is also observed for a wide variety of drugs. The enzymes involved in hydrolysis are esterases, amidases, and proteases. These reactions generate hydroxyl or amine groups, which are suitable for phase II conjugation. Phase II conjugation introduces hydrophilic functionalities such as glucuronic acid, sulfate, glycine, or acetyl group onto the drug or drug metabolite molecules. These reactions are catalyzed by a group of enzymes called transferases. Most trasferases are located in cytosol, except the one facilitates glucuronidation, which is a microsomal enzyme. This enzyme, called uridine diphosphate glucuronosyltransferase (UGTs), catalyzes the most important phase II reaction: glucuronidation. Glucuronic acid contains a number of hydroxyl groups and one carboxylic acid functionality. This molecule is extremely hydrophilic, and improves the hydrophilicity of a drug molecule when they are covalently bound. The following is a partial list of common metabolism motifs : 1. 2. 3. 4. 5. 6. Aliphatic/Aromatic carbons: hydroxylation. Methoxyl/methylamine group: demethylation. Amine: N-oxidation, or deamination. Sulfur: S-oxidation. Phenol/alcohol: glucuronidation/sulphation. Esters/amides: hydrolysis. V. The top changes that occur and their mass shifts Below is a brief list of mass shifts caused by metabolism of common functional groups. 1. 2. 3. 4. 5. Glucuronidation: plus 176 u. Sulfation: plus 80 u. Oxidation (N-, S-): plus 16 u. Hydroxylation (aliphatic, aromatic): plus 16 u (or 32, if two sites). Dealkylation: minus the alkyl group: minus 14 u for a methyl group, and 28 u for an ethyl group. 6. Hydrolysis: minus R-1 for ester hydrolysis into the acid. VI. Conclusion In reality, drug metabolism is an extremely complicated process, and the picture can be very messy. Often, a drug is metabolized into many products, some major, others minor. A complete picture of the metabolism of a drug is, in many cases, not possible, and not usually necessary. Abstract Drug-metabolizing enzymes are called mixed-function oxidase or monooxygenase and containing many enzymes including cytochrome P450, cytochrome b5, and NADPHcytochrome P450 reductase and other components. The hepatic cytochrome P450s (Cyp) are a multigene family of enzymes that play a critical role in the metabolism of many drugs and xenobiotics with each cytochrome isozyme responding differently to exogenous chemicals in terms of its induction and inhibition. For example, Cyp 1A1 is particularly active towards polycyclic aromatic hydrocarbons (PAHs), activating them into reactive intermediates those covalently bind to DNA, a key event in the initiation of carcinogenesis. Likewise, Cyp 1A2 activates a variety of bladder carcinogens, such as aromatic amines and amides. Also, some forms of cytochrome P450 isozymes such as Cyp 3A and 2E1 activate the naturally occurring carcinogens (e.g. aflatoxin B1) and Nnitrosamines respectively into highly mutagenic and carcinogenic agents. The carcinogenic potency of PAHs, and other carcinogens and the extent of binding of their ultimate metabolites to DNA and proteins are correlated with the induction of cytochrome P450 isozymes. Phase II drug-metabolizing enzymes such as glutathione S-transferase, aryl sulfatase and UDP-glucuronyl transferase inactivate chemical carcinogens into less toxic or inactive metabolites. Many drugs change the rate of activation or detoxification of carcinogens by changing the activities of phases I and II drug-metabolizing enzymes. The balance of detoxification and activation reactions depends on the chemical structure of the agents, and is subjected to many variables that are a function of this structure, or genetic background, sex, endocrine status, age, diet, and the presence of other chemicals. It is important to realize that the enzymes involved in carcinogen metabolism are also involved in the metabolism of a variety of substrates, and thus the introduction of specific xenobiotics may change the operating level and the existence of other chemicals. The mechanisms of modification of drugmetabolizing enzyme activities and their role in the activation and detoxification of xenobiotics and carcinogens have been discussed in the text. Drug metabolism Drug metabolism is the metabolism of drugs, their biochemical modification or degradation, usually through specialized enzymatic systems. This is a form of xenobiotic metabolism. Drug metabolism often converts lipophilic chemical compounds into more readily excreted polar products. Its rate is an important determinant of the duration and intensity of the pharmacological action of drugs. Drug metabolism can result in toxication or detoxication - the activation or deactivation of the chemical. While both occur, the major metabolites of most drugs are detoxication products. Drugs are almost all xenobiotics. Other commonly used organic chemicals are also xenobiotics, and are metabolized by the same enzymes as drugs. This provides the opportunity for drug-drug and drug-chemical interactions or reactions. Phase I vs. Phase II Phase I reactions usually precede Phase II, though not necessarily. During these reactions, polar bodies are either introduced or unmasked, which results in (more) polar metabolites of the original chemicals. In the case of pharmaceutical drugs, Phase I reactions can lead either to activation or inactivation of the drug. Phase I reactions (also termed nonsynthetic reactions) may occur by oxidation, reduction, hydrolysis, cyclization, and decyclization reactions. Oxidation involves the enzymatic addition of oxygen or removal of hydrogen, carried out by mixed function oxidases, often in the liver. These oxidative reactions typically involve a cytochrome P450 monooxygenase (often abbreviated CYP), NADPH and oxygen. The classes of pharmaceutical drugs that utilize this method for their metabolism include phenothiazines, paracetamol, and steroids. If the metabolites of phase I reactions are sufficiently polar, they may be readily excreted at this point. However, many phase I products are not eliminated rapidly and undergo a subsequent reaction in which an endogenous substrate combines with the newly incorporated functional group to form a highly polar conjugate. A common Phase I oxidation involves conversion of a C-H bond to a C-OH. This reaction sometimes converts a pharmacologically inactive compound (a prodrug) to a pharmacologically active one. By the same token, Phase I can turn a nontoxic molecule into a poisonous one (toxification). A famous example is acetonitrile, CH3CN. Simple hydrolysis in the stomach transforms acetonitrile into acetate and ammonia, which are comparatively innocuous. But Phase I metabolism converts acetonitrile to HOCH2CN, which rapidly dissociates into formaldehyde and hydrogen cyanide, both of which are toxic. Phase I metabolism of drug candidates can be simulated in the laboratory using non-enzyme catalysts.[1] This example of a biomimetic reaction tends to give a mixture of products that often contains the Phase I metabolites. Phase II reactions — usually known as conjugation reactions (e.g., with glucuronic acid, sulfonates (commonly known as sulfation) , glutathione or amino acids) — are usually detoxication in nature, and involve the interactions of the polar functional groups of phase I metabolites. Sites on drugs where conjugation reactions occur include carboxyl (-COOH), hydroxyl (-OH), amino (NH2), and sulfhydryl (-SH) groups. Products of conjugation reactions have increased molecular weight and are usually inactive unlike Phase I reactions which often produce active metabolites. Sites Quantitatively, the smooth endoplasmic reticulum of the liver cell is the principal organ of drug metabolism, although every biological tissue has some ability to metabolize drugs. Factors responsible for the liver's contribution to drug metabolism include that it is a large organ, that it is the first organ perfused by chemicals absorbed in the gut, and that there are very high concentrations of most drug-metabolizing enzyme systems relative to other organs. If a drug is taken into the GI tract, where it enters hepatic circulation through the portal vein, it becomes well-metabolized and is said to show the first pass effect. Other sites of drug metabolism include epithelial cells of the gastrointestinal tract, lungs, kidneys, and the skin. These sites are usually responsible for localized toxicity reactions. Major enzymes and pathways Several major enzymes and pathways are involved in drug metabolism, and can be divided into Phase I and Phase II reactions: Phase I Oxidation Cytochrome P450 monooxygenase system Flavin-containing monooxygenase system Alcohol dehydrogenase and aldehyde dehydrogenase Monoamine oxidase Co-oxidation by peroxidases Reduction NADPH-cytochrome P450 reductase Reduced (ferrous) cytochrome P450 It should be noted that during reduction reactions, a chemical can enter futile cycling, in which it gains a free-radical electron, then promptly loses it to oxygen (to form a superoxide anion). Hydrolysis Esterases and amidases Epoxide hydrolase Phase II Methylation methyltransferase Sulphation Glutathione S-transferases Sulfotransferases Acetylation N-acetyltransferases Amino acid N-acyl transferases Glucuronidation UDP-glucuronosyltransferases o Mercapturic acid biosynthesis Factors that affect Drug Metabolism The duration and intensity of pharmacological action of most lipophilic drugs are determined by the rate they are metabolized to inactive products. The Cytochrome P450 monooxygenase system is the most important pathway in this regard. In general, anything that increases the rate of metabolism (e.g., enzyme induction) of a pharmacologically active metabolite will decrease the duration and intensity of the drug action. The opposite is also true (e.g., enzyme inhibition). Various physiological and pathological factors can also affect drug metabolism. Physiological factors that can influence drug metabolism include age, individual variation (e.g., pharmacogenetics), enterohepatic circulation, nutrition, intestinal flora, or sex differences. In general, drugs are metabolized more slowly in fetal, neonatal and elderly humans and animals than in adults. Genetic variation (polymorphism) accounts for some of the variability in the effect of drugs. With N-acetyltransferases (involved in Phase II reactions), individual variation creates a group of people who acetylate slowly (slow acetylators) and those who acetylate quickly, split roughly 50:50 in the population of Canada. This variation may have dramatic consequences, as the slow acetylators are more prone to dose-dependent toxicity. Cytochrome P450 monooxygenase system enzymes can also vary across individuals, with deficiencies occurring in 1 - 30% of people, depending on their ethnic background. Pathological factors can also influence drug metabolism, including liver, kidney, or heart diseases. In silico modelling and simulation methods allow drug metabolism to be predicted in virtual patient populations prior to performing clinical studies in human subjects.[2] This can be used to identify individuals most at risk from adverse reaction.