Ergot
Ergot or ergot fungi refers to a group of fungi of the genus Claviceps. The most prominent member of this group is Claviceps purpurea; this fungus grows on rye and related plants, produces alkaloids that can cause ergotism in humans and other mammals who consume grains contaminated with its fruiting structure. Claviceps includes about 50 known species in the tropical regions. Economically significant species include C. purpurea, C. fusiformis, C. paspali, C. africana, C. lutea. C. purpurea most affects outcrossing species such as rye, as well as triticale and barley. It affects oats only rarely. C. purpurea has at least three races or varieties, which differ in their host specificity: G1 — land grasses of open meadows and fields. An ergot kernel, called a sclerotium, develops when a spore of fungal species of the genus Claviceps infects a floret of flowering grass or cereal; the infection process mimics a pollen grain growing into an ovary during fertilization. Infection requires; the proliferating fungal mycelium destroys the plant ovary and connects with the vascular bundle intended for seed nutrition.
The first stage of ergot infection manifests itself as a white soft tissue producing sugary honeydew, which drops out of the infected grass florets. This honeydew contains millions of asexual spores; the sphacelia convert into a hard dry sclerotium inside the husk of the floret. At this stage and lipids accumulate in the sclerotium. Claviceps species from tropic and subtropic regions produce macro- and microconidia in their honeydew. Macroconidia differ in shape and size between the species, whereas microconidia are rather uniform, oval to globose. Macroconidia are able to produce secondary conidia. A germ tube emerges from a macroconidium through the surface of a honeydew drop and a secondary conidium of an oval to pearlike shape is formed, to which the contents of the original macroconidium migrates. Secondary conidia form a frost-like surface on honeydew drops and spread via the wind. No such process occurs in Claviceps purpurea, Claviceps grohii, Claviceps nigricans, Claviceps zizaniae, all from northern temperate regions.
When a mature sclerotium drops to the ground, the fungus remains dormant until proper conditions trigger its fruiting phase. It germinates, forming several fruiting bodies with heads and stipes, variously coloured. In the head, threadlike sexual spores form, which are ejected when suitable grass hosts are flowering. Ergot infection causes a reduction in the yield and quality of grain and hay, if livestock eat infected grain or hay it may cause a disease called ergotism. Black and protruding sclerotia of C. purpurea are well known. However, many tropical ergots have brown or greyish sclerotia. For this reason, the infection is overlooked. Insects, including flies and moths, carry conidia of Claviceps species, but it is unknown whether insects play a role in spreading the fungus from infected to healthy plants; the evolution of plant parasitism in the Clavicipitaceae dates back at least 100 million years, to the early-mid Cretaceous. An amber fossil discovered in 2014 preserves an ergot-like parasitic fungus.
The fossil shows. The discovery establishes a minimum time for the conceivable presence of psychotropic compounds in fungi. Several evolutionary processes have acted to diversify the array of ergot alkaloids produced by fungi; the “old yellow enzyme,” EasA, presents an outstanding example. This enzyme catalyzes reduction of the C8=C9 double-bond in chanoclavine I, but EasA isoforms differ in whether they subsequently catalyze reoxidation of C8–C9 after rotation; this difference distinguishes most Clavicipitaceae from Trichocomaceae, but in Clavicipitaceae it is the key difference dividing the branch of classical ergot alkaloids from dihydroergot alkaloids, the latter being preferred for pharmaceuticals due to their few side effects. The ergot sclerotium contains high concentrations of the alkaloid ergotamine, a complex molecule consisting of a tripeptide-derived cyclol-lactam ring connected via amide linkage to a lysergic acid moiety, other alkaloids of the ergoline group that are biosynthesized by the fungus.
Ergot alkaloids have a wide range of biological activities including effects on circulation and neurotransmission. Ergot alkaloids are classified as: derivatives of 6,8-dimethylergoline and lysergic acid derivatives. Ergotism is the name for sometimes severe pathological syndromes affecting humans or other animals that have ingested plant material containing ergot alkaloid, such as ergot-contaminated grains; the Hospital Brothers of St. Anthony, an order of monks established in 1095, specialized in treating ergotism victims with balms containing tranquilizing and circulation-stimulating plant extracts; the common na
United States Adopted Name
United States Adopted Names are unique nonproprietary names assigned to pharmaceuticals marketed in the United States. Each name is assigned by the USAN Council, co-sponsored by the American Medical Association, the United States Pharmacopeial Convention, the American Pharmacists Association; the USAN Program states that its goal is to select simple and unique nonproprietary names for drugs by establishing logical nomenclature classifications based on pharmacological or chemical relationships. In addition to drugs, the USAN Council names agents for gene therapy and cell therapy, contact lens polymers, surgical materials, diagnostics and substances used as an excipient; the USAN Council works in conjunction with the World Health Organization International Nonproprietary Name Expert Committee and national nomenclature groups to standardize drug nomenclature and establish rules governing the classification of new substances. The USAN Council began in June 1961 after the AMA and the USP jointly formed the AMA-USP Nomenclature Committee.
The American Pharmacists Association became the third sponsoring organization in 1964, at which point the name of the committee was changed to the USAN Council, United States Adopted Name became the official term to describe any nonproprietary name negotiated and formally adopted by the Council. In 1967, a liaison representative from the Food and Drug Administration was appointed to serve on the USAN Council; the FDA announced in 1984 that it would discontinue adding drug names to its official list and use the USAN as the established name for labeling and advertising new single-entity drugs marketed in the United States. The AMA Council on Drugs no longer exists as a separate entity. FDA now has a representative on the USAN Council, which has moved away from chemically derived names; the USAN Council has five members, one from each sponsoring organization, one from the FDA, a member-at-large. One member is nominated to the USAN Council annually by each sponsoring organization; the member-at-large is selected by the sponsoring organizations from a list of candidates proposed by the AMA, APhA, the USP.
The five nominees to the Council must be approved annually by the board of trustees of the three sponsoring organizations. Judith Jones Thomas P. Reinders David Lewis Peter Rheinstein, Chair Armen Melikian By definition, nonproprietary names are not subject to proprietary trademark rights but are in the public domain; this distinguishes them from the trademarked names. Assignment of a USAN takes into account practical considerations, such as the existence of trademarks, international harmonization of drug nomenclature, the development of new classes of drugs, the fact that the intended uses of substances for which names are being selected may change. USANs assigned today reflect both present nomenclature practices and older methods used to name drug entities. Early drug nomenclature was based on the chemical structure; as newer drugs became chemically more complex and numerous, nonproprietary names based on chemistry became long and difficult to spell, pronounce, or remember. Additionally, chemically derived names provided little useful information to non-chemist health practitioners.
Considering the needs of health professionals led to a system in which USANs reflect relationships between new entities and older drugs, avoid names that might suggest non-existent relationships. Current nomenclature practices involve the adoption of standardized syllables called "stems" that relate new chemical entities to existing drug families. Stems may be suffixes, or infixes in the nonproprietary name; each stem can emphasize a specific chemical structure type, a pharmacologic property, or a combination of these attributes. The recommended list of USAN stems is updated to keep pace to accommodate drugs with new chemical and pharmacologic properties; as a general rule, the application for a USAN should be forwarded to the USAN Council after the Investigational New Drug is active and clinical trials have begun. Many drug manufacturers seeking a USAN are multinational companies with subsidiaries in various parts of the world or contractual agreements with drug firms outside the United States.
Therefore, it is desirable to the pharmaceutical company, the various nomenclature committees, the medical community in general that a global name be established for each new single-entity compound introduced. Assigning a USAN and standardizing names internationally can take anywhere from several months to a few years. Examples of drugs for which the USAN differs from the INN include: British Approved Name International Nonproprietary Name Nomenclature of monoclonal antibodies United States Pharmacopeia US Adopted Names Program
Salt (chemistry)
In chemistry, a salt is an ionic compound that can be formed by the neutralization reaction of an acid and a base. Salts are composed of related numbers of cations and anions so that the product is electrically neutral; these component ions can be inorganic, such as organic, such as acetate. Salts can be classified in a variety of ways. Salts that produce hydroxide ions when dissolved in water are called alkali salts. Salts that produce acidic solutions are acidic salts. Neutral salts are those salts that are neither basic. Zwitterions contain an anionic and a cationic centres in the same molecule, but are not considered to be salts. Examples of zwitterions include amino acids, many metabolites and proteins. Solid salts tend to be transparent. In many cases, the apparent opacity or transparency are only related to the difference in size of the individual monocrystals. Since light reflects from the grain boundaries, larger crystals tend to be transparent, while the polycrystalline aggregates look like white powders.
Salts exist in many different colors, which arise either from the cations. For example: sodium chromate is yellow by virtue of the chromate ion potassium dichromate is orange by virtue of the dichromate ion cobalt nitrate is red owing to the chromophore of hydrated cobalt. copper sulfate is blue because of the copper chromophore potassium permanganate has the violet color of permanganate anion. Nickel chloride is green of sodium chloride, magnesium sulfate heptahydrate are colorless or white because the constituent cations and anions do not absorb in the visible part of the spectrumFew minerals are salts because they would be solubilized by water. Inorganic pigments tend not to be salts, because insolubility is required for fastness; some organic dyes are salts, but they are insoluble in water. Different salts can elicit all five basic tastes, e.g. salty, sour and umami or savory. Salts of strong acids and strong bases are non-volatile and odorless, whereas salts of either weak acids or weak bases may smell like the conjugate acid or the conjugate base of the component ions.
That slow, partial decomposition is accelerated by the presence of water, since hydrolysis is the other half of the reversible reaction equation of formation of weak salts. Many ionic compounds exhibit significant solubility in water or other polar solvents. Unlike molecular compounds, salts dissociate in solution into cationic components; the lattice energy, the cohesive forces between these ions within a solid, determines the solubility. The solubility is dependent on how well each ion interacts with the solvent, so certain patterns become apparent. For example, salts of sodium and ammonium are soluble in water. Notable exceptions include potassium cobaltinitrite. Most nitrates and many sulfates are water-soluble. Exceptions include barium sulfate, calcium sulfate, lead sulfate, where the 2+/2− pairing leads to high lattice energies. For similar reasons, most alkali metal carbonates are not soluble in water; some soluble carbonate salts are: potassium carbonate and ammonium carbonate. Salts are characteristically insulators.
Molten salts or solutions of salts conduct electricity. For this reason, liquified salts and solutions containing dissolved salts are called electrolytes. Salts characteristically have high melting points. For example, sodium chloride melts at 801 °C; some salts with low lattice energies are liquid near room temperature. These include molten salts, which are mixtures of salts, ionic liquids, which contain organic cations; these liquids exhibit unusual properties as solvents. The name of a salt starts with the name of the cation followed by the name of the anion. Salts are referred to only by the name of the cation or by the name of the anion. Common salt-forming cations include: Ammonium NH+4 Calcium Ca2+ Iron Fe2+ and Fe3+ Magnesium Mg2+ Potassium K+ Pyridinium C5H5NH+ Quaternary ammonium NR+4, R being an alkyl group or an aryl group Sodium Na+ Copper Cu2+Common salt-forming anions include: Acetate CH3COO− Carbonate CO2−3 Chloride Cl− Citrate HOC2 Cyanide C≡N− Fluoride F− Nitrate NO−3 Nitrite NO−2 Oxide O2− Phosphate PO3−4 Sulfate SO2−4 Salts with varying number of hydrogen atoms, with respect to the parent acid, replaced by cations can be referred to as monobasic, dibasic or tribasic salts: Sodium phosphate monobasic Sodium phosphate dibasic Sodium phosphate tribasic Salts are formed by a chemical reaction between: A base and an acid, e.g. NH3 + HCl → NH4Cl A metal and an acid, e.g. Mg + H2SO4 → MgSO4 + H2 A metal and a non-metal, e.g. Ca + Cl2 → CaCl2 A base and an a
European Chemicals Agency
The European Chemicals Agency is an agency of the European Union which manages the technical and administrative aspects of the implementation of the European Union regulation called Registration, Evaluation and Restriction of Chemicals. ECHA is the driving force among regulatory authorities in implementing the EU's chemicals legislation. ECHA helps companies to comply with the legislation, advances the safe use of chemicals, provides information on chemicals and addresses chemicals of concern, it is located in Finland. The agency headed by Executive Director Bjorn Hansen, started working on 1 June 2007; the REACH Regulation requires companies to provide information on the hazards and safe use of chemical substances that they manufacture or import. Companies register this information with ECHA and it is freely available on their website. So far, thousands of the most hazardous and the most used substances have been registered; the information is technical but gives detail on the impact of each chemical on people and the environment.
This gives European consumers the right to ask retailers whether the goods they buy contain dangerous substances. The Classification and Packaging Regulation introduces a globally harmonised system for classifying and labelling chemicals into the EU; this worldwide system makes it easier for workers and consumers to know the effects of chemicals and how to use products safely because the labels on products are now the same throughout the world. Companies need to notify ECHA of the labelling of their chemicals. So far, ECHA has received over 5 million notifications for more than 100 000 substances; the information is available on their website. Consumers can check chemicals in the products. Biocidal products include, for example, insect disinfectants used in hospitals; the Biocidal Products Regulation ensures that there is enough information about these products so that consumers can use them safely. ECHA is responsible for implementing the regulation; the law on Prior Informed Consent sets guidelines for the import of hazardous chemicals.
Through this mechanism, countries due to receive hazardous chemicals are informed in advance and have the possibility of rejecting their import. Substances that may have serious effects on human health and the environment are identified as Substances of Very High Concern 1; these are substances which cause cancer, mutation or are toxic to reproduction as well as substances which persist in the body or the environment and do not break down. Other substances considered. Companies manufacturing or importing articles containing these substances in a concentration above 0,1% weight of the article, have legal obligations, they are required to inform users about the presence of the substance and therefore how to use it safely. Consumers have the right to ask the retailer whether these substances are present in the products they buy. Once a substance has been identified in the EU as being of high concern, it will be added to a list; this list is available on ECHA's website and shows consumers and industry which chemicals are identified as SVHCs.
Substances placed on the Candidate List can move to another list. This means that, after a given date, companies will not be allowed to place the substance on the market or to use it, unless they have been given prior authorisation to do so by ECHA. One of the main aims of this listing process is to phase out SVHCs where possible. In its 2018 substance evaluation progress report, ECHA said chemical companies failed to provide “important safety information” in nearly three quarters of cases checked that year. "The numbers show a similar picture to previous years" the report said. The agency noted that member states need to develop risk management measures to control unsafe commercial use of chemicals in 71% of the substances checked. Executive Director Bjorn Hansen called non-compliance with REACH a "worry". Industry group CEFIC acknowledged the problem; the European Environmental Bureau called for faster enforcement to minimise chemical exposure. European Chemicals Bureau Official website
Alkaloid
Alkaloids are a class of occurring organic compounds that contain basic nitrogen atoms. This group includes some related compounds with neutral and weakly acidic properties; some synthetic compounds of similar structure may be termed alkaloids. In addition to carbon and nitrogen, alkaloids may contain oxygen, sulfur and, more other elements such as chlorine and phosphorus. Alkaloids are produced by a large variety of organisms including bacteria, fungi and animals, they can be purified from crude extracts of these organisms by acid-base extraction. Alkaloids have a wide range of pharmacological activities including antimalarial, anticancer, vasodilatory, analgesic and antihyperglycemic activities. Many have found use as starting points for drug discovery. Other alkaloids possess psychotropic and stimulant activities, have been used in entheogenic rituals or as recreational drugs. Alkaloids can be toxic too. Although alkaloids act on a diversity of metabolic systems in humans and other animals, they uniformly evoke a bitter taste.
The boundary between alkaloids and other nitrogen-containing natural compounds is not clear-cut. Compounds like amino acid peptides, nucleotides, nucleic acid and antibiotics are not called alkaloids. Natural compounds containing nitrogen in the exocyclic position are classified as amines rather than as alkaloids; some authors, consider alkaloids a special case of amines. The name "alkaloids" was introduced in 1819 by the German chemist Carl Friedrich Wilhelm Meißner, is derived from late Latin root alkali and the suffix -οειδής – "like". However, the term came into wide use only after the publication of a review article by Oscar Jacobsen in the chemical dictionary of Albert Ladenburg in the 1880s. There is no unique method of naming alkaloids. Many individual names are formed by adding the suffix "ine" to the genus name. For example, atropine is isolated from the plant Atropa belladonna. Where several alkaloids are extracted from one plant their names are distinguished by variations in the suffix: "idine", "anine", "aline", "inine" etc.
There are at least 86 alkaloids whose names contain the root "vin" because they are extracted from vinca plants such as Vinca rosea. Alkaloid-containing plants have been used by humans since ancient times for therapeutic and recreational purposes. For example, medicinal plants have been known in the Mesopotamia at least around 2000 BC; the Odyssey of Homer referred to a gift given to Helen by the Egyptian queen, a drug bringing oblivion. It is believed. A Chinese book on houseplants written in 1st–3rd centuries BC mentioned a medical use of Ephedra and opium poppies. Coca leaves have been used by South American Indians since ancient times. Extracts from plants containing toxic alkaloids, such as aconitine and tubocurarine, were used since antiquity for poisoning arrows. Studies of alkaloids began in the 19th century. In 1804, the German chemist Friedrich Sertürner isolated from opium a "soporific principle", which he called "morphium" in honor of Morpheus, the Greek god of dreams; the term "morphine", used in English and French, was given by the French physicist Joseph Louis Gay-Lussac.
A significant contribution to the chemistry of alkaloids in the early years of its development was made by the French researchers Pierre Joseph Pelletier and Joseph Bienaimé Caventou, who discovered quinine and strychnine. Several other alkaloids were discovered around that time, including xanthine, caffeine, nicotine, colchicine and cocaine; the development of the chemistry of alkaloids was accelerated by the emergence of spectroscopic and chromatographic methods in the 20th century, so that by 2008 more than 12,000 alkaloids had been identified. The first complete synthesis of an alkaloid was achieved in 1886 by the German chemist Albert Ladenburg, he produced coniine by reacting 2-methylpyridine with acetaldehyde and reducing the resulting 2-propenyl pyridine with sodium. Compared with most other classes of natural compounds, alkaloids are characterized by a great structural diversity. There is no uniform classification; when knowledge of chemical structures was lacking, botanical classification of the source plants was relied on.
This classification is now considered obsolete. More recent classifications are based on similarity of the carbon biochemical precursor. However, they require compromises in borderline cases. Alkaloids are divided into the following major groups: "True alkaloids" contain nitrogen in the heterocycle and originate from amino acids, their characteristic examples are atropine and morphine. This group a
Biosynthesis
Biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined together to form macromolecules; this process consists of metabolic pathways. Some of these biosynthetic pathways are located within a single cellular organelle, while others involve enzymes that are located within multiple cellular organelles. Examples of these biosynthetic pathways include the production of lipid membrane components and nucleotides. Biosynthesis is synonymous with anabolism; the prerequisite elements for biosynthesis include: precursor compounds, chemical energy, catalytic enzymes which may require coenzymes. These elements create the building blocks for macromolecules; some important biological macromolecules include: proteins, which are composed of amino acid monomers joined via peptide bonds, DNA molecules, which are composed of nucleotides joined via phosphodiester bonds.
Biosynthesis occurs due to a series of chemical reactions. For these reactions to take place, the following elements are necessary: Precursor compounds: these compounds are the starting molecules or substrates in a reaction; these may be viewed as the reactants in a given chemical process. Chemical energy: chemical energy can be found in the form of high energy molecules; these molecules are required for energetically unfavorable reactions. Furthermore, the hydrolysis of these compounds drives a reaction forward. High energy molecules, such as ATP, have three phosphates; the terminal phosphate is split off during hydrolysis and transferred to another molecule. Catalytic enzymes: these molecules are special proteins that catalyze a reaction by increasing the rate of the reaction and lowering the activation energy. Coenzymes or cofactors: cofactors are molecules that assist in chemical reactions; these may be metal ions, vitamin derivatives such as NADH and acetyl CoA, or non-vitamin derivatives such as ATP.
In the case of NADH, the molecule transfers a hydrogen, whereas acetyl CoA transfers an acetyl group, ATP transfers a phosphate. In the simplest sense, the reactions that occur in biosynthesis have the following format: Reactant → e n z y m e Product Some variations of this basic equation which will be discussed in more detail are: Simple compounds which are converted into other compounds as part of a multiple step reaction pathway. Two examples of this type of reaction occur during the formation of nucleic acids and the charging of tRNA prior to translation. For some of these steps, chemical energy is required: Precursor molecule + ATP ↽ − − ⇀ product AMP + PP i Simple compounds that are converted into other compounds with the assistance of cofactors. For example, the synthesis of phospholipids requires acetyl CoA, while the synthesis of another membrane component, requires NADH and FADH for the formation the sphingosine backbone; the general equation for these examples is: Precursor molecule + Cofactor → e n z y m e macromolecule Simple compounds that join together to create a macromolecule.
For example, fatty acids join together to form phospholipids. In turn and cholesterol interact noncovalently in order to form the lipid bilayer; this reaction may be depicted as follows: Molecule 1 + Molecule 2 ⟶ macromolecule Many intricate macromolecules are synthesized in a pattern of simple, repeated structures. For example, the simplest structures of lipids are fatty acids. Fatty acids are hydrocarbon derivatives; these fatty acids create larger components, which in turn incorporate noncovalent interactions to form the lipid bilayer. Fatty acid chains are found in two major components of membrane lipids: phospholipids and sphingolipids. A third major membrane component, does not contain these fatty acid units; the foundation of all biomembranes consists of a bilayer structure of phospholipids. The phospholipid molecule is amphipathic; the phospholipid heads interact with each other and aqueous media, while the hydrocarbon tails orient themselves in the center, away from water. These latter interactions drive the bilayer structure that acts as a barrier for molecules.
There are various types of phospholipids. However, the first step in phospholipid synthesis involves the formation of phosphatidate or diacylglycerol 3-phosphate at the endoplasmic reticulum and outer mitochondrial membrane; the synthesis pathway is found below: The pathway starts with glycerol 3-phosphate, which gets converted to lysophosphatidate via the addition of a fatty acid chain provided by acyl coenzyme A. Then, lysophosphatidate is converted to phosphatidate via the addition of another fatty acid chain contributed by a second acyl CoA.
Pharmacokinetics
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to determine the fate of substances administered to a living organism. The substances of interest include any chemical xenobiotic such as: pharmaceutical drugs, food additives, etc, it attempts to analyze chemical metabolism and to discover the fate of a chemical from the moment that it is administered up to the point at which it is eliminated from the body. Pharmacokinetics is the study of how an organism affects a drug, whereas pharmacodynamics is the study of how the drug affects the organism. Both together influence dosing and adverse effects, as seen in PK/PD models. Pharmacokinetics describes how the body affects a specific xenobiotic/chemical after administration through the mechanisms of absorption and distribution, as well as the metabolic changes of the substance in the body, the effects and routes of excretion of the metabolites of the drug. Pharmacokinetic properties of chemicals are affected by the route of administration and the dose of administered drug.
These may affect the absorption rate. Models have been developed to simplify conceptualization of the many processes that take place in the interaction between an organism and a chemical substance. One of these, the multi-compartmental model, is the most used approximations to reality; the various compartments that the model is divided into are referred to as the ADME scheme: Liberation – the process of release of a drug from the pharmaceutical formulation. See IVIVC. Absorption – the process of a substance entering the blood circulation. Distribution – the dispersion or dissemination of substances throughout the fluids and tissues of the body. Metabolism – the recognition by the organism that a foreign substance is present and the irreversible transformation of parent compounds into daughter metabolites. Excretion – the removal of the substances from the body. In rare cases, some drugs irreversibly accumulate in body tissue; the two phases of metabolism and excretion can be grouped together under the title elimination.
The study of these distinct phases involves the use and manipulation of basic concepts in order to understand the process dynamics. For this reason in order to comprehend the kinetics of a drug it is necessary to have detailed knowledge of a number of factors such as: the properties of the substances that act as excipients, the characteristics of the appropriate biological membranes and the way that substances can cross them, or the characteristics of the enzyme reactions that inactivate the drug. All these concepts can be represented through mathematical formulas that have a corresponding graphical representation; the use of these models allows an understanding of the characteristics of a molecule, as well as how a particular drug will behave given information regarding some of its basic characteristics such as its acid dissociation constant and solubility, absorption capacity and distribution in the organism. The model outputs for a drug can be used in industry or in the clinical application of pharmacokinetic concepts.
Clinical pharmacokinetics provides many performance guidelines for effective and efficient use of drugs for human-health professionals and in veterinary medicine. The following are the most measured pharmacokinetic metrics: In pharmacokinetics, steady state refers to the situation where the overall intake of a drug is in dynamic equilibrium with its elimination. In practice, it is considered that steady state is reached when a time of 4 to 5 times the half-life for a drug after regular dosing is started; the following graph depicts a typical time course of drug plasma concentration and illustrates main pharmacokinetic metrics: Pharmacokinetic modelling is performed by noncompartmental or compartmental methods. Noncompartmental methods estimate the exposure to a drug by estimating the area under the curve of a concentration-time graph. Compartmental methods estimate the concentration-time graph using kinetic models. Noncompartmental methods are more versatile in that they do not assume any specific compartmental model and produce accurate results acceptable for bioequivalence studies.
The final outcome of the transformations that a drug undergoes in an organism and the rules that determine this fate depend on a number of interrelated factors. A number of functional models have been developed in order to simplify the study of pharmacokinetics; these models are based on a consideration of an organism as a number of related compartments. The simplest idea is to think of an organism as only one homogenous compartment; this monocompartmental model presupposes that blood plasma concentrations of the drug are a true reflection of the drug's concentration in other fluids or tissues and that the elimination of the drug is directly proportional to the drug's concentration in the organism. However, these models do not always reflect the real situation within an organism. For example, not all body tissues have the same blood supply, so the distribution of the drug will be slower in these tissues than in others with a better blood supply. In addition, there are some tissues (s
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