In biochemistry, allosteric regulation is the regulation of an enzyme by binding an effector molecule at a site other than the enzyme's active site. The site to which the effector binds is termed regulatory site. Allosteric sites allow effectors to bind to the protein resulting in a conformational change involving protein dynamics. Effectors that enhance the protein's activity are referred to as allosteric activators, whereas those that decrease the protein's activity are called allosteric inhibitors. Allosteric regulations are a natural example of control loops, such as feedback from downstream products or feedforward from upstream substrates. Long-range allostery is important in cell signaling. Allosteric regulation is particularly important in the cell's ability to adjust enzyme activity; the term allostery comes from the Ancient Greek allos, "other", stereos, "solid". This is in reference to the fact that the regulatory site of an allosteric protein is physically distinct from its active site.
Many allosteric effects can be explained by the concerted MWC model put forth by Monod and Changeux, or by the sequential model described by Koshland and Filmer. Both postulate that protein subunits exist in one of two conformations, tensed or relaxed, that relaxed subunits bind substrate more than those in the tense state; the two models differ most in their assumptions about subunit interaction and the preexistence of both states. For proteins in which subunits exist in more than two conformations, the allostery landscape model described by Cuendet, LeVine, can be used; the concerted model of allostery referred to as the symmetry model or MWC model, postulates that enzyme subunits are connected in such a way that a conformational change in one subunit is conferred to all other subunits. Thus, all subunits must exist in the same conformation; the model further holds that, in the absence of any ligand, the equilibrium favors one of the conformational states, T or R. The equilibrium can be shifted to the R or T state through the binding of one ligand to a site, different from the active site.
The sequential model of allosteric regulation holds that subunits are not connected in such a way that a conformational change in one induces a similar change in the others. Thus, all enzyme subunits do not necessitate the same conformation. Moreover, the sequential model dictates that molecules of a substrate bind via an induced fit protocol. In general, when a subunit randomly collides with a molecule of substrate, the active site, in essence, forms a glove around its substrate. While such an induced fit converts a subunit from the tensed state to relaxed state, it does not propagate the conformational change to adjacent subunits. Instead, substrate-binding at one subunit only alters the structure of other subunits so that their binding sites are more receptive to substrate. To summarize: subunits need not exist in the same conformation molecules of substrate bind via induced-fit protocol conformational changes are not propagated to all subunits The morpheein model of allosteric regulation is a dissociative concerted model.
A morpheein is a homo-oligomeric structure that can exist as an ensemble of physiologically significant and functionally different alternate quaternary assemblies. Transitions between alternate morpheein assemblies involve oligomer dissociation, conformational change in the dissociated state, reassembly to a different oligomer; the required oligomer disassembly step differentiates the morpheein model for allosteric regulation from the classic MWC and KNF models. Porphobilinogen synthase is the prototype morpheein. Ensemble models of allosteric regulation enumerate an allosteric system's statistical ensemble as a function of its potential energy function, relate specific statistical measurements of allostery to specific energy terms in the energy function. Ensemble models like the ensemble allosteric model and allosteric Ising model assume that each domain of the system can adopt two states similar to the MWC model; the allostery landscape model introduced by Cuendet, LeVine allows for the domains to have any number of states and the contribution of a specific molecular interaction to a given allosteric coupling can be estimated using a rigorous set of rules.
Molecular dynamics simulations can be used to estimate a system's statistical ensemble so that it can be analyzed with the allostery landscape model. Allosteric modulation is used to alter the activity of molecules and enzymes in biochemistry and pharmacology. For comparison, a typical drug is made to bind to the active site of an enzyme which thus prohibits binding of a substrate to that enzyme causing a decrease in enzyme activity. Allosteric modulation occurs when an effector binds to an allosteric site of an enzyme and alters the enzyme activity. Allosteric modulators are designed to fit the allosteric site to cause a conformational change of the enzyme, in particular a change in the shape of the active site, which causes a change in its activity. In contrast to typical drugs, modulators are not competitive inhibitors, they can be positive causing an increase of the enzyme activity or negative causing a decrease of the enzyme activity. The use of allosteric modulation allows the control of the effects of specific enzyme activities.
An example of this model is seen with the Mycobacterium tuberculosis, a bacterium, s
The Who are an English rock band formed in London in 1964. Their classic line-up consisted of lead singer Roger Daltrey and singer Pete Townshend, bass guitarist John Entwistle and drummer Keith Moon, they are considered one of the most influential rock bands of the 20th century, selling over 100 million records worldwide. The Who developed from an earlier group, the Detours, established themselves as part of the pop art and mod movements, featuring auto-destructive art by destroying guitars and drums on stage, their first single as the Who, "I Can't Explain", reached the UK top ten, followed by a string of singles including "My Generation", "Substitute" and "Happy Jack". In 1967, they performed at the Monterey Pop Festival and released the US top ten single "I Can See for Miles", while touring extensively; the group's fourth album, 1969's rock opera Tommy, included the single "Pinball Wizard" and was a critical and commercial success. Live appearances at Woodstock and the Isle of Wight Festival, along with the live album Live at Leeds, cemented their reputation as a respected rock act.
With their success came increased pressure on lead songwriter Townshend, the follow-up to Tommy, was abandoned. Songs from the project made up 1971's Who's Next, which included the hit "Won't Get Fooled Again"; the group released the album Quadrophenia in 1973 as a celebration of their mod roots, oversaw the film adaptation of Tommy in 1975. They continued to tour to large audiences before semi-retiring from live performances at the end of 1976; the release of Who Are You in 1978 was overshadowed by the death of Moon shortly after. Kenney Jones replaced Moon and the group resumed activity, releasing a film adaptation of Quadrophenia and the retrospective documentary The Kids Are Alright. After Townshend became weary of touring, the group split in 1983; the Who re-formed for live appearances such as Live Aid in 1985, a 25th anniversary tour in 1989 and a tour of Quadrophenia in 1996–1997. They resumed regular touring with drummer Zak Starkey. After Entwistle's death in 2002, plans for a new album were delayed.
Townshend and Daltrey continued as the Who, releasing Endless Wire in 2006, continue to play live with Starkey, bassists Pino Palladino and Jon Button, guitarist Simon Townshend serving as touring players. A tour with a complete symphony orchestra, along with a planned studio album, are both scheduled for 2019; the Who's major contributions to rock music include the development of the Marshall stack, large PA systems, use of the synthesizer and Moon's lead playing styles, Townshend's feedback and power chord guitar technique, the development of the rock opera. They are cited as an influence by hard rock, punk rock and mod bands, their songs still receive regular exposure; the founder members of the Who, Roger Daltrey, Pete Townshend and John Entwistle, grew up in Acton and went to Acton County Grammar School. Townshend's father, played saxophone and his mother, had sung in the entertainment division of the Royal Air Force during World War II, both supported their son's interest in rock and roll.
Townshend and Entwistle became friends in their second year of Acton County, formed a trad jazz group. Both were interested in rock, Townshend admired Cliff Richard's début single, "Move It". Entwistle moved to guitar, but struggled with it due to his large fingers, moved to bass on hearing the guitar work of Duane Eddy, he built one at home. After Acton County, Townshend attended Ealing Art College, a move he described as profoundly influential on the course of the Who. Daltrey, in the year above, had moved to Acton from Shepherd's Bush, a more working-class area, he had trouble fitting in at the school, discovered gangs and rock and roll. He found work on a building site. In 1959 he started the Detours, the band, to evolve into the Who; the band played professional gigs, such as corporate and wedding functions, Daltrey kept a close eye on the finances as well as the music. Daltrey spotted Entwistle by chance on the street carrying a bass and recruited him into the Detours. In mid-1961, Entwistle suggested Townshend as a guitarist, Daltrey on lead guitar, Entwistle on bass, Harry Wilson on drums, Colin Dawson on vocals.
The band played instrumentals by the Shadows and the Ventures, a variety of pop and trad jazz covers. Daltrey was considered the leader and, according to Townshend, "ran things the way he wanted them". Wilson was fired in mid-1962 and replaced by Doug Sandom, though he was older than the rest of the band, a more proficient musician, having been playing semi-professionally for two years. Dawson left after arguing with Daltrey and after being replaced by Gabby Connolly, Daltrey moved to lead vocals. Townshend, with Entwistle's encouragement, became the sole guitarist. Through Townshend's mother, the group obtained a management contract with local promoter Robert Druce, who started booking the band as a support act; the Detours were influenced by the bands they supported, including Screaming Lord Sutch, Cliff Bennett and the Rebel Rousers, Shane Fenton and the Fentones, Johnny Kidd and the Pirates. The Detours were interested in the Pirates as they only had one guitarist, Mick Green, who inspired Townshend to combine rhythm and lead guitar in his style.
Entwistle's bass became more of a lead instrument. In February 1964, the Detours became aware of the group Johnny Devlin and the Detours and changed their name. Townshend and his room-mate Richard Barnes spent a night c
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
Simplified molecular-input line-entry system
The simplified molecular-input line-entry system is a specification in the form of a line notation for describing the structure of chemical species using short ASCII strings. SMILES strings can be imported by most molecule editors for conversion back into two-dimensional drawings or three-dimensional models of the molecules; the original SMILES specification was initiated in the 1980s. It has since been extended. In 2007, an open standard called. Other linear notations include the Wiswesser line notation, ROSDAL, SYBYL Line Notation; the original SMILES specification was initiated by David Weininger at the USEPA Mid-Continent Ecology Division Laboratory in Duluth in the 1980s. Acknowledged for their parts in the early development were "Gilman Veith and Rose Russo and Albert Leo and Corwin Hansch for supporting the work, Arthur Weininger and Jeremy Scofield for assistance in programming the system." The Environmental Protection Agency funded the initial project to develop SMILES. It has since been modified and extended by others, most notably by Daylight Chemical Information Systems.
In 2007, an open standard called "OpenSMILES" was developed by the Blue Obelisk open-source chemistry community. Other'linear' notations include the Wiswesser Line Notation, ROSDAL and SLN. In July 2006, the IUPAC introduced the InChI as a standard for formula representation. SMILES is considered to have the advantage of being more human-readable than InChI; the term SMILES refers to a line notation for encoding molecular structures and specific instances should be called SMILES strings. However, the term SMILES is commonly used to refer to both a single SMILES string and a number of SMILES strings; the terms "canonical" and "isomeric" can lead to some confusion when applied to SMILES. The terms are not mutually exclusive. A number of valid SMILES strings can be written for a molecule. For example, CCO, OCC and CC all specify the structure of ethanol. Algorithms have been developed to generate the same SMILES string for a given molecule; this SMILES is unique for each structure, although dependent on the canonicalization algorithm used to generate it, is termed the canonical SMILES.
These algorithms first convert the SMILES to an internal representation of the molecular structure. Various algorithms for generating canonical SMILES have been developed and include those by Daylight Chemical Information Systems, OpenEye Scientific Software, MEDIT, Chemical Computing Group, MolSoft LLC, the Chemistry Development Kit. A common application of canonical SMILES is indexing and ensuring uniqueness of molecules in a database; the original paper that described the CANGEN algorithm claimed to generate unique SMILES strings for graphs representing molecules, but the algorithm fails for a number of simple cases and cannot be considered a correct method for representing a graph canonically. There is no systematic comparison across commercial software to test if such flaws exist in those packages. SMILES notation allows the specification of configuration at tetrahedral centers, double bond geometry; these are structural features that cannot be specified by connectivity alone and SMILES which encode this information are termed isomeric SMILES.
A notable feature of these rules is. The term isomeric SMILES is applied to SMILES in which isotopes are specified. In terms of a graph-based computational procedure, SMILES is a string obtained by printing the symbol nodes encountered in a depth-first tree traversal of a chemical graph; the chemical graph is first trimmed to remove hydrogen atoms and cycles are broken to turn it into a spanning tree. Where cycles have been broken, numeric suffix labels are included to indicate the connected nodes. Parentheses are used to indicate points of branching on the tree; the resultant SMILES form depends on the choices: of the bonds chosen to break cycles, of the starting atom used for the depth-first traversal, of the order in which branches are listed when encountered. Atoms are represented by the standard abbreviation of the chemical elements, in square brackets, such as for gold. Brackets may be omitted in the common case of atoms which: are in the "organic subset" of B, C, N, O, P, S, F, Cl, Br, or I, have no formal charge, have the number of hydrogens attached implied by the SMILES valence model, are the normal isotopes, are not chiral centers.
All other elements must be enclosed in brackets, have charges and hydrogens shown explicitly. For instance, the SMILES for water may be written as either O or. Hydrogen may be written as a separate atom; when brackets are used, the symbol H is added if the atom in brackets is bonded to one or more hydrogen, followed by the number of hydrogen atoms if greater than 1 by the sign + for a positive charge or by - for a negative charge. For example, for ammonium. If there is more than one charge, it is written as digit.
In chemistry, an alcohol is any organic compound in which the hydroxyl functional group is bound to a carbon. The term alcohol referred to the primary alcohol ethanol, used as a drug and is the main alcohol present in alcoholic beverages. An important class of alcohols, of which methanol and ethanol are the simplest members, includes all compounds for which the general formula is CnH2n+1OH, it is these simple monoalcohols. The suffix -ol appears in the IUPAC chemical name of all substances where the hydroxyl group is the functional group with the highest priority; when a higher priority group is present in the compound, the prefix hydroxy- is used in its IUPAC name. The suffix -ol in non-IUPAC names typically indicates that the substance is an alcohol. However, many substances that contain hydroxyl functional groups have names which include neither the suffix -ol, nor the prefix hydroxy-. Alcohol distillation originated in India. During 2000 BCE, people of India used. Alcohol distillation was known to Islamic chemists as early as the eighth century.
The Arab chemist, al-Kindi, unambiguously described the distillation of wine in a treatise titled as "The Book of the chemistry of Perfume and Distillations". The Persian physician, alchemist and philosopher Rhazes is credited with the discovery of ethanol; the word "alcohol" is from a powder used as an eyeliner. Al- is the Arabic definite article, equivalent to the in English. Alcohol was used for the fine powder produced by the sublimation of the natural mineral stibnite to form antimony trisulfide Sb2S3, it was considered to be the essence or "spirit" of this mineral. It was used as an antiseptic and cosmetic; the meaning of alcohol was extended to distilled substances in general, narrowed to ethanol, when "spirits" was a synonym for hard liquor. Bartholomew Traheron, in his 1543 translation of John of Vigo, introduces the word as a term used by "barbarous" authors for "fine powder." Vigo wrote: "the barbarous auctours use alcohol, or alcofoll, for moost fine poudre."The 1657 Lexicon Chymicum, by William Johnson glosses the word as "antimonium sive stibium."
By extension, the word came to refer to any fluid obtained by distillation, including "alcohol of wine," the distilled essence of wine. Libavius in Alchymia refers to "vini alcohol vel vinum alcalisatum". Johnson glosses alcohol vini as "quando omnis superfluitas vini a vino separatur, ita ut accensum ardeat donec totum consumatur, nihilque fæcum aut phlegmatis in fundo remaneat." The word's meaning became restricted to "spirit of wine" in the 18th century and was extended to the class of substances so-called as "alcohols" in modern chemistry after 1850. The term ethanol was invented 1892, combining the word ethane with the "-ol" ending of "alcohol". IUPAC nomenclature is used in scientific publications and where precise identification of the substance is important in cases where the relative complexity of the molecule does not make such a systematic name unwieldy. In naming simple alcohols, the name of the alkane chain loses the terminal e and adds the suffix -ol, e.g. as in "ethanol" from the alkane chain name "ethane".
When necessary, the position of the hydroxyl group is indicated by a number between the alkane name and the -ol: propan-1-ol for CH3CH2CH2OH, propan-2-ol for CH3CHCH3. If a higher priority group is present the prefix hydroxy-is used, e.g. as in 1-hydroxy-2-propanone. In cases where the OH functional group is bonded to an sp2 carbon on an aromatic ring the molecule is known as a phenol, is named using the IUPAC rules for naming phenols. In other less formal contexts, an alcohol is called with the name of the corresponding alkyl group followed by the word "alcohol", e.g. methyl alcohol, ethyl alcohol. Propyl alcohol may be n-propyl alcohol or isopropyl alcohol, depending on whether the hydroxyl group is bonded to the end or middle carbon on the straight propane chain; as described under systematic naming, if another group on the molecule takes priority, the alcohol moiety is indicated using the "hydroxy-" prefix. Alcohols are classified into primary and tertiary, based upon the number of carbon atoms connected to the carbon atom that bears the hydroxyl functional group.
The primary alcohols have general formulas RCH2OH. The simplest primary alcohol is methanol, for which R=H, the next is ethanol, for which R=CH3, the methyl group. Secondary alcohols are those of the form RR'CHOH, the simplest of, 2-propanol. For the tertiary alcohols the general form is RR'R"COH; the simplest example is tert-butanol, for which each of R, R', R" is CH3. In these shorthands, R, R', R" represent substituents, alkyl or other attached organic groups. In archaic nomenclature, alcohols can be named as derivatives of methanol using "-carbinol" as the ending. For instance, 3COH can be named trimethylcarbinol. Alcohols have a long history of myriad uses. For simple mono-alcohols, the focus on this article, the following are most important industrial alcohols: methanol for the production of formaldehyde and as a fuel additive ethanol for alcoholic beverages, fuel additive, solvent 1-propanol, 1-butanol, isobutyl alcohol for use as a solvent a
The United Kingdom the United Kingdom of Great Britain and Northern Ireland, sometimes referred to as Britain, is a sovereign country located off the north-western coast of the European mainland. The United Kingdom includes the island of Great Britain, the north-eastern part of the island of Ireland, many smaller islands. Northern Ireland is the only part of the United Kingdom that shares a land border with another sovereign state, the Republic of Ireland. Apart from this land border, the United Kingdom is surrounded by the Atlantic Ocean, with the North Sea to the east, the English Channel to the south and the Celtic Sea to the south-west, giving it the 12th-longest coastline in the world; the Irish Sea lies between Great Ireland. With an area of 242,500 square kilometres, the United Kingdom is the 78th-largest sovereign state in the world, it is the 22nd-most populous country, with an estimated 66.0 million inhabitants in 2017. The UK is constitutional monarchy; the current monarch is Queen Elizabeth II, who has reigned since 1952, making her the longest-serving current head of state.
The United Kingdom's capital and largest city is London, a global city and financial centre with an urban area population of 10.3 million. Other major urban areas in the UK include Greater Manchester, the West Midlands and West Yorkshire conurbations, Greater Glasgow and the Liverpool Built-up Area; the United Kingdom consists of four constituent countries: England, Scotland and Northern Ireland. Their capitals are London, Edinburgh and Belfast, respectively. Apart from England, the countries have their own devolved governments, each with varying powers, but such power is delegated by the Parliament of the United Kingdom, which may enact laws unilaterally altering or abolishing devolution; the nearby Isle of Man, Bailiwick of Guernsey and Bailiwick of Jersey are not part of the UK, being Crown dependencies with the British Government responsible for defence and international representation. The medieval conquest and subsequent annexation of Wales by the Kingdom of England, followed by the union between England and Scotland in 1707 to form the Kingdom of Great Britain, the union in 1801 of Great Britain with the Kingdom of Ireland created the United Kingdom of Great Britain and Ireland.
Five-sixths of Ireland seceded from the UK in 1922, leaving the present formulation of the United Kingdom of Great Britain and Northern Ireland. There are fourteen British Overseas Territories, the remnants of the British Empire which, at its height in the 1920s, encompassed a quarter of the world's land mass and was the largest empire in history. British influence can be observed in the language and political systems of many of its former colonies; the United Kingdom is a developed country and has the world's fifth-largest economy by nominal GDP and ninth-largest economy by purchasing power parity. It has a high-income economy and has a high Human Development Index rating, ranking 14th in the world, it was the world's first industrialised country and the world's foremost power during the 19th and early 20th centuries. The UK remains a great power, with considerable economic, military and political influence internationally, it is sixth in military expenditure in the world. It has been a permanent member of the United Nations Security Council since its first session in 1946.
It has been a leading member state of the European Union and its predecessor, the European Economic Community, since 1973. The United Kingdom is a member of the Commonwealth of Nations, the Council of Europe, the G7, the G20, NATO, the Organisation for Economic Co-operation and Development and the World Trade Organization; the 1707 Acts of Union declared that the kingdoms of England and Scotland were "United into One Kingdom by the Name of Great Britain". The term "United Kingdom" has been used as a description for the former kingdom of Great Britain, although its official name from 1707 to 1800 was "Great Britain"; the Acts of Union 1800 united the kingdom of Great Britain and the kingdom of Ireland in 1801, forming the United Kingdom of Great Britain and Ireland. Following the partition of Ireland and the independence of the Irish Free State in 1922, which left Northern Ireland as the only part of the island of Ireland within the United Kingdom, the name was changed to the "United Kingdom of Great Britain and Northern Ireland".
Although the United Kingdom is a sovereign country, Scotland and Northern Ireland are widely referred to as countries. The UK Prime Minister's website has used the phrase "countries within a country" to describe the United Kingdom; some statistical summaries, such as those for the twelve NUTS 1 regions of the United Kingdom refer to Scotland and Northern Ireland as "regions". Northern Ireland is referred to as a "province". With regard to Northern Ireland, the descriptive name used "can be controversial, with the choice revealing one's political preferences"; the term "Great Britain" conventionally refers to the island of Great Britain, or politically to England and Wales in combination. However, it is sometimes used as a loose synonym for the United Kingdom as a whole; the term "Britain" is used both as a synonym for Great Britain, as a synonym for the United Kingdom. Usage is mixed, with the BBC preferring to use Britain as shorthand only for Great Britain and the UK Government, while accepting that both terms refer to the United K
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