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Drug metabolism is the metabolism of drugs, their biochemical modification or degradation, usually through specialized enzymatic systems. Metabolism is the set of Chemical reactions that occur in living Organisms in order to maintain Life. Medication, also referred to as medicine, can be loosely defined as any substance intended for use in the diagnosis cure mitigation treatment or prevention of disease Biochemistry is the study of the chemical processes in living Organisms It deals with the Structure and function of cellular components such as Enzymes are Biomolecules that catalyze ( ie increase the rates of Chemical reactions Almost all enzymes are Proteins This is a form of xenobiotic metabolism. Xenobiotic metabolism is the set of Metabolic pathways that modify the chemical structure of Xenobiotics which are compounds foreign to an organism's normal biochemistry Drug metabolism often converts lipophilic chemical compounds into more readily excreted polar products. In Chemistry, hydrophobicity (from the combining form of water in Attic Greek hydro- and for fear phobos) refers to the physical property of A chemical compound is a substance consisting of two or more different elements chemically bonded together in a fixed proportion by Mass. Excretion is the process of eliminating waste products of Metabolism and other non-useful materials Hydrophile, from the Greek (hydros "water" and φιλια (philia "friendship" refers to a physical property of a Molecule 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. Medication, also referred to as medicine, can be loosely defined as any substance intended for use in the diagnosis cure mitigation treatment or prevention of disease Toxication is the process of Metabolism in which the metabolite of a compound is more toxic than the parent drug or Chemical. Detoxication products are the major metabolites formed from most Drug metabolism. While both occur, the major metabolites of most drugs are detoxication products.

Drugs are almost all xenobiotics. A xenobiotic is a Chemical which is found in an Organism but which is not normally produced or expected to be present in it Other commonly used organic chemicals are also xenobiotics, and are metabolized by the same enzymes as drugs. An organic compound is any member of a large class of Chemical compounds whose Molecules contain Carbon. Enzymes are Biomolecules that catalyze ( ie increase the rates of Chemical reactions Almost all enzymes are Proteins This provides the opportunity for drug-drug and drug-chemical interactions or reactions. A drug interaction is a situation in which a substance affects the activity of a drug, i A drug interaction is a situation in which a substance affects the activity of a drug, i

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Phase I vs. Phase II

Phase I and Phase II reactions are biotransformations of chemicals that occur during drug metabolism. Biotransformation is the chemical modification (or modifications made by an organism on a chemical compound

Phase I reactions usually precedes 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. Redox (shorthand for reduction-oxidation reaction describes all Chemical reactions in which atoms have their Oxidation number ( Oxidation state Redox (shorthand for reduction-oxidation reaction describes all Chemical reactions in which atoms have their Oxidation number ( Oxidation state Hydrolysis is a Chemical reaction during which one or more water molecules are split into hydrogen and hydroxide ions which may go on to participate in further 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 haemoprotein, NADPH and oxygen. Cytochrome P450 (abbreviated CYP, P450, infrequently CYP450) is a very large and diverse superfamily of Hemoproteins found in all Domains The classes of pharmaceutical drugs that utilize this method for their metabolism include phenothiazines, paracetamol, and steroids. Paracetamol ( INN) (ˌpærəˈsiːtəmɒl -ˈsɛtə- or acetaminophen ( USAN) is a widely-used Analgesic and Antipyretic Medication 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.

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. Glucuronic acid (from Greek γλυκερός - "sweet" is a Carboxylic acid. Sulfonic acid is an unstable Acid with the formula H-S(=O2-OH Glutathione ( GSH) is a Tripeptide. It contains an unusual Peptide linkage between the amine group of Cysteine and the Carboxyl In Chemistry, an amino acid is a Molecule containing both Amine and Carboxyl Functional groups In Biochemistry, this Detoxication products are the major metabolites formed from most Drug metabolism.

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. The endoplasmic reticulum (Greek endo = "within" (prefix plásma = "formed entity" Latin reticulum = "little net" or ER, is an Organelle The liver is a vital organ in the human body and is present in Vertebrates and some other animals Tissue is a cellular organizational level intermediate between cells and a complete organism 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. The first-pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of Drug metabolism whereby the Concentration

Other sites of drug metabolism include epithelial cells of the gastrointestinal tract, lungs, kidneys, and the skin. In biology and medicine epithelium is a tissue composed of cells that line the cavities and surfaces of structures throughout the body lung is the essential Respiration organ in air-breathing Animals including most Tetrapods a few Fish and a few Snails The most primitive The kidneys are complicated organs that have numerous biological roles The skin is the outer covering of living tissue of an animal (or plant 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

Reduction

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). Cytochrome P450 (abbreviated CYP, P450, infrequently CYP450) is a very large and diverse superfamily of Hemoproteins found in all Domains The flavin-containing monooxygenase (FMO Protein family consists of a group of Enzymes that catalyze chemical reactions via the bound Cofactor Flavin Alcohol dehydrogenase (ADH is an enzyme discovered in the mid-1960s in Drosophila melanogaster. Aldehyde dehydrogenases, EC 1213, are a group of Enzymes that Catalyse the Oxidation (dehydrogenation of Aldehydes Mitochrondrial Peroxidases ( EC number 1111x are a large family of Enzymes A majority of peroxidase protein sequences can be found in the PeroxiBase database Oxygen (from the Greek roots ὀξύς (oxys (acid literally "sharp" from the taste of acids and -γενής (-genēs (producer literally begetteris the

Hydrolysis

Phase II

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. An esterase is a Hydrolase Enzyme that splits Esters into an Acid and an Alcohol in a Chemical reaction with water Epoxide hydrolase (also known as Epoxide hydratase functions in Detoxication during Drug metabolism. The glutathione S -transferase (GST family of Enzymes comprises a long list of Cytosolic, Mitochondrial, and Microsomal Uridine 5'-diphospho-glucuronosyltransferase ( UDP -glucuronosyltransferase UGT is a Glycosyltransferase ( that catalyzes the Glucuronidation N-acetyltransferase is an Enzyme that catalyzes the transfer of Acetyl groups from Acetyl-CoA to Arylamines They have wide specificity Sulfotransferase s are Transferase enzymes that catalyze the transfer of a sulfate group from a donor molecule to an acceptor alcohol or amine The Cytochrome P450 monooxygenase system is the most important pathway in this regard. Cytochrome P450 (abbreviated CYP, P450, infrequently CYP450) is a very large and diverse superfamily of Hemoproteins found in all Domains 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. Enzyme inhibitors are Molecules that bind to Enzymes and decrease their activity. The opposite is also true (e. g. , enzyme inhibition). Enzyme inhibitors are Molecules that bind to Enzymes and decrease their activity.

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. The terms Pharmacogenomics and pharmacogenetics tend to be used interchangeably and a precise consensus definition of either remains elusive Enterohepatic circulation refers to the circulation of Bile from the Liver, where it is produced to the Small intestine, where it aids in Digestion Nutrition (also called nourishment or aliment) is the provision to cells and Organisms of the materials necessary (in the form of food to support The gut flora are the Microorganisms that normally live in the Digestive tract and can perform a number of useful functions for their hosts Sexual dimorphism is the systematic difference in form between individuals of different Sex in the same Species.

In general, drugs are metabolized more slowly in fetal, neonatal and elderly humans and animals than in adults. A fetus (or foetus or fœtus) is a developing Mammal or other Viviparous Vertebrate, after the Embryonic stage and Old age consists of ages nearing or surpassing the Average life span of Human beings and thus the end of the human life cycle. Human beings, humans or man (Origin 1590–1600 L homō man OL hemō the earthly one (see Humus For the 2008 British film by Noel Clarke see Adulthood (film.

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. Country to "Dominion of Canada" or "Canadian Federation" or anything else please read the Talk Page 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. Cytochrome P450 (abbreviated CYP, P450, infrequently CYP450) is a very large and diverse superfamily of Hemoproteins found in all Domains

Pathological factors can also influence drug metabolism, including liver, kidney, or heart diseases. The liver is a vital organ in the human body and is present in Vertebrates and some other animals The kidneys are complicated organs that have numerous biological roles The heart is a muscular organ in all Vertebrates responsible for pumping Blood through the Blood vessels by repeated rhythmic

In silico modelling and simulation methods allow drug metabolism to be predicted in virtual patient populations prior to performing clinical studies in human subjects. [1]. This can be used to identify individuals most at risk from adverse reaction.


See also


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References

  1. ^ Amin Rostami-Hodjegan; Geoffrey Tucker (2007). A prodrug is a pharmacological substance ( drug) that is administered in an inactive (or significantly less active form The Simcyp population-based ADME simulator is a modelling and simulation platform used by the pharmaceutical industry in drug discovery and development "Simulation and prediction of in vivo drug metabolism in human populations from in vitro data". Nature Reviews Drug Discovery 6 (2): 140-148. doi:10.1038/nrd2173. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document.  
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