History of paleontology in the United States

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https://en.wikipedia.org/wiki/History_of_paleontology_in_the_United_States 

 

Exhuming the First American Mastodon, oil on canvas by Charles Willson Peale (1806).

The history of paleontology in the United States refers to the developments and discoveries regarding fossils found within or by people from the United States of America. Local paleontology began informally with Native Americans, who have been familiar with fossils for thousands of years. They both told myths about them and applied them to practical purposes. African slaves also contributed their knowledge; the first reasonably accurate recorded identification of vertebrate fossils in the new world was made by slaves on a South Carolina plantation who recognized the elephant affinities of mammoth molars uncovered there in 1725. The first major fossil discovery to attract the attention of formally trained scientists were the Ice Age fossils of Kentucky's Big Bone Lick. These fossils were studied by eminent intellectuals like France's George Cuvier and local statesmen and frontiersman like Daniel Boone, Benjamin Franklin, William Henry Harrison, Thomas Jefferson, and George Washington. By the end of the 18th century possible dinosaur fossils had already been found.

By the beginning of the 19th, their fossil footprints definitely had. Later in the century as more dinosaur fossils were uncovered eminent paleontologists Edward Drinker Cope and Othniel Charles Marsh were embroiled in a bitter rivalry to collect the most fossils and name the most new prehistoric species. Early in the 20th century major finds continued, like the Ice Age mammals of the La Brea Tar Pits, the Oligocene bonebeds of South Dakota, and the Triassic bonebeds of New Mexico. Mid-to-late twentieth century discoveries in the United States triggered the Dinosaur Renaissance as the discovery of the bird-like Deinonychus overturned misguided notions of dinosaurs as plodding lizard-like animals, cemented their sophisticated physiology and relationship with birds. Other notable finds include Maiasaura, which provided early evidence for parental care in dinosaurs and "Seismosaurus" the largest known dinosaur.

Indigenous interpretations

Fossils of large Ice Age birds like Teratornis may have inspired Native American Thunderbird legends.

The indigenous people of the United States interpreted the fossil record through a mythological lens. Some of the tactics they used to understand the fossil record were nevertheless similar to scientific approaches. Native American fossil legends often derived from observation and rational speculation based on fossil finds. The indigenous people of the United States also frequently attempted to verify and modify interpretations of the fossil record in order to make sense of new discoveries. Although imperfect, Native American oral histories can preserve accurate information for extended periods of time. Since contact with Europeans, the ensuing epidemics, colonial violence, the Indian Wars, and forced displacement of Native peoples to reservations has resulted in the loss of much of their fossil-related culture.^[2] According to folklorist Adrienne Mayor, a common theme in indigenous American fossil legends is "the eternal struggle for natural balance among earth, water and sky forces". Indigenous fossil legends also frequently show motifs resembling major themes in scientific paleontology like deep time, extinction, change over time and relationships between different life forms. Fossils have been used by Native Americans for evidence about the past, healing, personal protection, and trade. Fossil sites were often chosen as the setting of vision quests. Modern Comanche in Oklahoma still use dinosaur and mammoth bones for medicinal purposes.

18th century

George Cuvier's illustration comparing the lower jaw of a wooly mammoth (above) and an Indian elephant (below).

The first reasonably correct identification of a vertebrate fossil in North America was made in 1725, at a South Carolina plantation called Stono. There slaves had uncovered several large fossil teeth while digging in a swamp. The slaves unanimously identified the teeth as elephant molars, which they would have recognized from life in Africa. In the early 19th century, Georges Cuvier authored an 1806 translated account of the discovery at Stono. He remarked that the African slaves understood the similarity between mammoth remains and elephants before European naturalists.

The first major vertebrate fossil discovery in North America to attract the attention of formally trainer scientists occurred just a few decades later. In July 1739 a French military expedition comprising 123 French soldiers and 319 Native American warriors left Quebec under the command of Charles III Le Moyne (2nd Baron Charles de Longueuil) to help defend New Orleans from the Chickasaw, who were attacking the city on behalf of England. While on their journey down the Ohio River towards the Mississippi, they camped in what is now Kentucky. Some of the expedition's Native members formed a hunting party and embarked to acquire that evening's meal. When they returned that evening their canoes were laden with massive fossils including long tusks, massive teeth, and a thighbone almost as tall as a person. The source of their fossils was the site now known as Big Bone Lick.

Near the end of 1740, Baron Charles de Longueuil departed from New Orleans to France, carrying with him fossils from Big Bone Lick. Longueuil left the remains at the Cabinet du Roi. This Cabinet du Roi (not to be confused with the administration personnel cabinet of the same name) was a collection of curiosities stored in the chateau of the king's botanical garden (which is nowadays the Jardin des plantes, in Paris, main seat of the French National Museum of Natural History). These fossils were first speculated on by eminent French scientists like Jean-Etienne Guettard and Georges Cuvier. A few years later, in 1762, Louis Daubenton read his paper before the French Royal Academy of Science showing that the bones and tusks belonged to an elephant-like species and that the teeth belonged to some kind of carnivorous hippopotamus. In fact the teeth belonged to the same individual, in the present day identified as an American mastodon (Mammut americanum).

In 1767 George Crogan (an Indian agent) sent several fossils from Big Bone Lick to Benjamin Franklin. Benjamin Franklin wrote back to express his amazement that the tusks resembled those of an elephant, yet the molars resembled those of a carnivorous animal. Franklin also wondered at the fact that the elephant-like fossils of Big Bone Lick were found in places so much colder than places modern elephants live. He speculated that maybe earth was in a different position in the past and its climate correspondingly different. Soon after the fossils attracted the attention of other major American figures like George Washington, Thomas Jefferson, Daniel Boone, William Henry Harrison, and James Taylor. The mammoth quickly became a symbol of American patriotism and equality with the Old World.

One of the earliest notable events in American dinosaur paleontology occurred on October 5, 1787. Caspar Wistar and Timothy Matlack gave a presentation to the American Philosophical Society in Philadelphia regarding "'a large thigh bone'" from some mysterious ancient creature found in Late Cretaceous rocks near Woodbury Creek, New Jersey. Modern scientist suspect this bone was actually a metatarsal from a duck-billed dinosaur, which are known from the same sediments.

19th century

A negative footprint of Grallator showing skin impressions.

Among the earliest major fossil discoveries in America occurred in Massachusetts during the spring of 1802. At that time a boy uncovered a piece of reddish sandstone with bird-like three toed footprints while ploughing on his father's farm in South Hadley. This was the first recorded dinosaur footprint discovery in North America. A short while later, Lewis and Clark expedition of 1804 through 1806 made several fossil discoveries along its journey, including the first documented fossils from what is now North Dakota. However, only a fish jawbone from Iowa remains of the fossils they collected along the way. Another significant, but unrelated event from the early 19th century was the 1817 organization of the Lyceum of Natural History of New York by Samuel L. Mitchill. In 1869 the American Museum of Natural History was organized out of the Lyceum.

During the Late 1830s Increase Allen Lapham found a variety of fossils in great abundance in some rocky hills near Milwaukee. Lapham sent a sizable sampling of the local fossils to James Hall of New York in 1846. Hall began researching the area and in 1862 recognized the local reefs for what they were. The Silurian-aged reefs of the Milwaukee area were the first Paleozoic reefs in the world to be described for the scientific literature.

In 1835 another major dinosaur track find occurred in Massachusetts. The town of Greenfield was paving its streets when residents noticed fossil footprints on the sandstone slabs that resembled turkey tracks. These rocks were taken from what would turn out to be the most productive dinosaur tracksite in the Connecticut Valley. Later that year, word of the find reached Amherst College geology professor Edward Hitchcock. Hitchcock spent the rest of the summer traveling through the Connecticut Valley examining the fossil footprints. The next year Hitchcock wrote a scientific paper on the fossil footprints of the Connecticut Valley. He thought the tracks were made by giant birds. In 1858, Hitchcock published again on the Connecticut Valley fossil footprints and still thought of them as bird tracks.

Basilosaurus.

In 1842, fossils were found on a plantation owned by a man named Judge Creagh. Local doctors identified the fossils as belonging to an ancient marine reptile, and called it Basilosaurus. However, some of the fossils were shipped to Sir Richard Owen in England. After examining the remains Owen realized the bones actually belonged to a whale, rather than a reptile. Herman Melville's narrator Ishmael gives an account of the discovery in chapters 104–105 of Moby-Dick (1851).

In 1853 the Pacific Railroad Exploration survey became the first to document Arizona's petrified forest. In 1900 the United States Geological Survey dedicated a report to the petrified forest and encouraged swift action to preserve the spectacular fossils before curiosity seekers removed them all. In 1906, protective action was taken and Petrified Forest officially became a national monument.

Benjamin Waterhouse Hawkins' mounted Hadrosaurus, the first mounted dinosaur skeleton in the world.

In 1858 the United States was home to the world's first "reasonably complete" dinosaur skeleton. A member of the Academy of Natural Sciences named William Foulke heard about fossil bones that had been found on a local farm while spending the summer in Haddonfield. That fall Foulke hired a team to reopen the marl pit the bones had been taken from. Roughly 10 feet down they found bones. Paleontologist Joseph Leidy later formally described the fossils. He interpreted the fossils as the remains of a bipedal amphibious reptile that had been swept out to sea by the river it lived alongside. Leidy called the creature Hadrosaurus foulkii after Foulke. A decade later, in 1868 Leidy worked with artist Benjamin Waterhouse Hawkins to mount Hadrosaurus foulkii for the Academy of Natural Sciences of Philadelphia. This became both the first mounted dinosaur skeleton ever mounted for public display but also one of the most popular exhibits in the history of the Academy. Estimates have the Hadrosaurus exhibit as increasing the number of visitors by up to 50%.

The year after the Hadrosaurus's fossils were first identified, 1859, state agricultural chemist Philip T. Tyson found the first documented dinosaur fossils of the Arundel Formation in an iron pit at Bladensburg, Maryland. The discovery consisted of two fossil teeth. Tyson took the dinosaur teeth to a local doctor named Christopher Johnston. Johnston cut thin sections of one tooth to examine it under a microscope. Johnson named the teeth Astrodon. In 1865 Joseph Leidy formally named the species Astrodon johnstoni after Christopher Johnston. This represents the first formal naming of a sauropod species in North America.

Two years later a chance find would bring instant fame to the fossils of the John Day region of Oregon. In 1861, a company of soldiers arrived in Oregon's Fort Dalles after visiting the Crooked River region brought back fossil bones and teeth, among which was a well-preserved rhinoceros jaw. The pastor of the fort's Congregational church, Thomas Condon, happened to be a paleontology enthusiast. In 1862, some soldiers were dispatched with supplies to Harney Valley. Condon went along with them and prospected for fossils when the troops passed back through the Crooked River area. He went fossil collecting again in 1863 and found rich fossil deposits north of Picture Gorge in the John Day River Valley. He realized that he had stumbled on a find of major scientific importance. Since he himself had no scientific qualifications or references to use in identifying fossils, Condon sent some fossils to O. C. Marsh of Yale University. Marsh replied with a request for Condon to guide and expedition to the area in which he found the fossils. Condon obliged and over the ensuing years a series of fossil hunting expeditions ventured into the John Day fossil beds.

An early painting of Laelaps/Dryptosaurus by Charles R. Knight.

Later, 1866 dinosaur remains were found in a marl pit near Barnsboro owned by the Wet Jersey Marl Company. He called it Laelaps aquilunguis. Also that year, Cope gave Othniel Charles Marsh a tour of the marl pit where Laelaps was found. While there, Marsh secretly made arrangements with some of the workers for them to send any fossils they find to him at the Yale Peabody Museum instead of to Cope at the Academy of Natural Sciences of Philadelphia. This may have been the "first shot" of the Bone Wars, a bitter long-running feud between the two scientists.

The next year a United States army surgeon named Dr. Theophilus Turner found a nearly complete plesiosaur skeleton in what is now Logan County while stationed at Fort Wallace. This was the first plesiosaur specimen of this caliber found in all of North America. Dr. Turner gave some of the vertebrae to a member of the Union Pacific railroad survey, John LeConte. He in turn gave the bones to paleontologist Edward Drinker Cope, who identified them as the remains of a very large plesiosaur. Cope wrote a letter to Dr. Turner requesting that he send him the remainder of the skeleton. Turner obliged and in mid-March 1868 Cope received the remainder of the fossils. Within two weeks of receiving the specimen, Cope made a presentation at the March 24th meeting of the Academy of Natural Sciences in Philadelphia. He named the creature Elasmosaurus platyurus, although in his hasty work he mistakenly reconstructed it with its head at the end of the tail instead of its neck.

In 1869, excavation started at Gilboa Forest, an extraordinary collection of Devonian plants regarded as one of the first forests to ever exist. Excavation of the Gilboa petrified forest continued on into the early twentieth century, but by 1921 on-site field work had completed.

Othniel Charles Marsh.

The next year, O. C. Marsh led a paleontological expedition into the western United States on behalf of Yale University. Late that November they visited the area around Fort Wallace. Among the fossils found by Marsh's crew in western Kansas were the far ends of two pterosaur wing metacarpals. These were the first scientifically documented fossils of the pterosaur that would later be named Pteranodon. This formal naming occurred six years later, in 1876.

In 1874 March's rival, Cope arrived at New Mexico accompanying the G. M. Wheeler Survey. While in the area he found the first known Eocene mammal from the southwestern United States, Coryphodon. In total he discovered about 90 species. This was a major boon to his reputation as his research was foundational to understanding that interval of American geologic history.

Around March 1877 a man named Oramel Lucas discovered sauropod bones in a valley called Garden Park located a few miles north of Canon City, Colorado. He wrote to both Cope and O. C. Marsh, the famous rival paleontologists of the bone wars to alert them about his discovery. Although Marsh never responded, Cope did, and Oramel Lucas and his brother Ira began digging up local fossils and sending them to Cope. By August of the same year, Cope had formally named the new species excavated by the Lucas brothers Camarasaurus supremus. Later, a crew working on behalf of O. C. Marsh under Mudge and Williston started a quarry nearby. They made several important finds like the new species Allosaurus fragilis and Diplodocus longus. Following the initial excavations in the quarry field work stopped until 1883. That year brothers Marshall and Henry Felch reopened excavations there, again on behalf of O. C. Marsh. They worked for five years collecting many dinosaurs already known from the formation, but also the new species Ceratosaurus nasicornis.

Beginning in 1877, the plentiful dinosaur remains preserved in Wyoming came to the attention of scientists. Three men played a pivotal early role in bringing scientific attention to the area's dinosaurs. These were Colorado School of Mines professor Arthur Lakes, teacher O. Lucas, and Union Pacific Railroad foreman William H. Reed. In March 1877, Reed noticed fossil limbs and vertebrae at Como Bluff. He spent several weeks collecting fossils with foreman William E. Carlin. In July, O. C. Marsh was informed of Reed and Carlin's fossil discoveries. Marsh hired both of them to acquire more local fossils for him. They continued collecting into early 1878, uncovering several Camarasaurus specimens, one being a new species, Camarasaurus grandis. Nearby they made another significant find, Dryolestes priscus, the first Jurassic mammal known from North America. From 1877 to 1878 Princeton also sent a massive expedition to Wyoming. Major participants included Henry Fairfield Osborn, W. E. Scott, and Thomas Speer. Also around this time, Samuel W. Williston began periodic excavations.

Edward Drinker Cope.

Late in 1877, Marsh's scientific rival Edward Drinker Cope heard that fossils had been found at Como Bluff. He quickly dispatched his own fossil hunters into the area. Reed described his struggles to keep Cope's men away from his own hunting grounds in regular correspondence with Marsh. William Carlin quit working for Marsh and ended up joining Cope's efforts in the region. Since Carlin was in charge of the railway's station house he used his influence to keep Reed out. Marsh hired additional help for Reed, but none of his workers stayed on the job long term. Reed was essentially on his own by the spring of 1879, working hectically at excavating several quarries at once to recover the fossils before Cope's men. In the middle of May that same year Marsh directed Arthur Lakes to leave the Morrison, Colorado area and assist Reed at Como Bluff. The partnership would be fruitful that year and several major discoveries happened. They found a ninth site early in July that would be the most productive of any fossil site in the Morrison Formation.

In September, they made another major discovery. By the end of the month, they had identified a new species of sauropod, Brontosaurus excelsus, that would end up mounted in the Yale Peabody Museum. This species has since been reclassified as Apatosaurus excelsus. In September they found a thirteenth quarry that produced more dinosaur skeletons than any of the others. Camptosaurus and Stegosaurus were the most common. New dinosaurs found here included Camarasaurus lentus, Camptosaurus dispar, and Coelurus fragilis. By June 1889, fieldwork at Como Bluff had concluded after twelve years. Marsh's fieldwork in the area uncovered the greatest abundance of Jurassic fossils known in the world at the time. By the 1918 conclusion of Samuel W. Williston's work in Wyoming hundreds of tons of dinosaur bones had been recovered from Wyoming rocks.

Diceratherium cooki.

A major Cenozoic fossil find also happened in 1877. That year, a scout and rancher named Captain James H. Cook found a Miocene bonebed in Sioux County, Nebraska now known as the Agate Springs Quarries. These rich deposits are so dense with bones that single forty foot slab of sandstone preserved more than 4300 bones from at least 1700 individual animals. The total number of fossils preserved here may number in the millions. The tiny rhinoceras Diceratherium cooki composed about one quarter of the remains in the Agate Springs beds. This was the first paleontological discovery to attract public attention to the fossils of Nebraska.

In late 1887 Othniel Charles Marsh sent John Bell Hatcher to look for dinosaur remains in the Arundel Clay. While on this expedition, Hatcher found a fossiliferous iron mine on a farm near Muikirk, Maryland. Hatcher's excavation continued uncovering dinosaur fossils into the next year. Hatcher recovered hundreds of bones and teeth, which helped the region between Maryland and Washington D.C. become known as Dinosaur Alley.

20th century

Barosaurus and Allosaurus mounted at the American Museum of Natural History.

Between 1906 and 1916 hundreds of thousands of Pleistocene fossils were uncovered in central Los Angeles. Just a few years after the La Brea tar pits were found, in 1908, paleontologist Earl Douglass was excavating fossils in Utah on behalf of the Carnegie Museum of Natural History. The director of the museum visited Douglass's camp that year and suggested that Douglass search for Jurassic dinosaur fossils in the Uinta Mountains north of his camp. Douglass agreed and they set off to the Uinta Mountains the next day. They found so many fossils that Douglas built a home near the Green River and his family moved in from Pittsburgh. He spent the rest of his career in the area excavating fossils. Among the local finds were Allosaurus, Apatosaurus, Barosaurus, Camarasaurus, Camptosaurus, Diplodocus, Dryosaurus, Stegosaurus. In 1915 US president Woodrow Wilson declared the quarry and surrounding land Dinosaur National Monument in order to protect it from settlement. Between 1909 and 1923 millions of tons of rocks and fossils had been excavated from the Dinosaur National Monument area.

In 1909 in paleontology Massachusetts paleontologist Mignon Talbot became the first woman elected to the Paleontological Society. In an unrelated east coast discovery of 1912, workers digging in a cave for a railroad construction project near Cumberland, Maryland in Allegany County uncovered many fossils in the course of their labor. However, eventually the scientific significance of the fossils was realized and paleontologist J. W. Gidley conducted fieldwork at the cave between 1912 and 1915. By 1938 report more than 50 different kinds of animals had been identified among the fossils.

Norman Ross preparing the skeleton of a baby Brachyceratops for exhibition in 1921.

In 1938, Barnum Brown of the American Museum of Natural History sent Roland T. Bird to Texas in search of dinosaur trackways reportedly uncovered by local moonshiners. At the town of Glen Rose local residents guided him to carnivorous dinosaur tracks preserved along the Paluxy River. While he was cleaning mud from these footprints, he noticed another kind of footprint, apparently left by a long-necked sauropod dinosaur. In 1940, Bird resumed his Texas fieldwork with the help of paleontologists from the Survey and labor employed by the Works Progress Administration.

Later, in 1940, the South Dakota School of Mines and Technology collaborated with National Geographic on an expedition into the badlands of South Dakota. They uncovered tons of fossils from at least 175 different species of Oligocene life. The fossils were taken to the South Dakota School of Mines in Rapid City. Among the mammal discoveries were the remains of rhinoceroses, tapirs, three-toed horses, pig-like animals, and rodents. In 1947 another major dinosaur discovery took place. An American Museum field party led by Edwin Harris Colbert found a bonebed including the skeletons of more than 1,000 Coelophysis at Ghost Ranch. Later, in 1953 University of New Mexico graduate student William Chenoweth found three important sites where dinosaurs were preserved in Morrison Formation rocks. He found a fragmentary Allosaurus, sauropods, and Stegosaurus.

Theropod and sauropod tracks under water in the Paluxy River.

The famous Montanan Tertiary deposits of the Ruby Valley basin were also first studied in 1947. The early research was performed by Dr. Herman F. Becker on behalf of the New York Botanical Garden. These deposits from the southwestern part of the state are one of the best sources of plant and insect fossils in North America. In 1959 Becker's Ruby Valley excavations uncovered about 5,000 specimens of more than two hundred species of plants, insects, and fishes. Invertebrate finds included ants, bees, beetles, earwigs, caddis flies, crane flies, damsel flies, lantern flies, may flies, grasshoppers, leaf hoppers, mosquitoes, snails, and wasps. Vertebrate remains included feathers, and, once in a while, a bird.

During the late 1950s Francis Tully found a fossil he could not identify at the strip mines near Braidwood, Illinois. He took the specimen to Chicago's Field Museum of Natural History. Researchers at the museum couldn't identify it either, and the specimen became known as Mr. Tully's monster. In 1966, Eugene Richardson, the Curator of Fossil Invertebrates of the Field Museum formally named the Tully monster Tullimonstrum gregarium in honor of Tully.

The bird-like dinosaur Deinonychus instigated the Dinosaur Renaissance.

In 1964, John Ostrom led an expedition that included his student Robert T. Bakker into the south-central part of Montana. The rocks they prospected were of the Cloverly Formation, dating back to the Early Cretaceous. Among their finds were the first documented remains of a small carnivorous dinosaur that would be named Deinonychus antirrhopus. This discovery helped ignite the Dinosaur Renaissance. It exhibited important anatomical similarities to birds that helped scientists shed antiquated ideas interpreting dinosaurs as "overgrown lizards".

In Spring, 1965 a major discovery of Devonian fossils occurred in Cuyahoga County. A collaboration between the state Highway Department, Ohio Bureau of Public Roads and the Cleveland Museum of Natural History led by the Smithsonian's David Dunkle uncovered as many as 50,000 fish fossils from a construction site. By the ensuing November 120 or more different species had been found there, with half previously unknown to science. That same year, in an unrelated development, the Florissant fossil beds of Colorado were proposed as a potential federal preserve.

The hadrosaur Maisaura may have cared for its young.

In 1978 paleontologist Bill Clemens alerted fellow paleontologists Jack Horner and Bob Makela to the presence of unidentified dinosaur fossils in Bynum, Montana. Horner visited the town and recognized the remains as belonging to a duck-billed dinosaur. While in town the owner of a local rock shop, Marion Brandvold, showed him some tiny bones. Horner identified them as baby duck-bill bones. Horner also knew that this was an important find and convinced Brandvold to donate her fossils to a museum. She obliged and gave them to Princeton University. Horner's team prospected in the area where Brandvold found the baby hadrosaur fossils. Their effort paid off with the discovery of the first scientifically documented dinosaur eggs of the Western Hemisphere and a new kind of duck-bill, Maiasaura peeblesorum.

The next year, 1979, two hikers found a series of gigantic articulated vertebrae fossils near San Ysidro. They reported the remains to David Gilette of the New Mexico Museum of Natural History. Gillette led an expedition into the region and used cutting edge technology to locate the remains while they were still entombed in sandstone. The team excavated a massive quarry and gradually recovered a significant portion of the rear half of a diplodocid sauropod dinosaur. In 1991 this dinosaur was formally described as the new genus Seismosaurus and estimated to be the longest dinosaur known to science at 52 meters (171 feet) long.

21st century

More recently, in the 2000s, Seismosaurus was found to be the same as Diplodocus, a previously known dinosaur of similar age from the western United States. Dinosaur fossils continue to be found in new locations within the United States. It was not until 2004 that any dinosaur fossils were reported from Louisiana. Currently, within the United States, dinosaur fossils are known from Alabama, Alaska, Arizona, Arkansas, California, Colorado, Connecticut, Delaware, Georgia, Idaho, Iowa, Kansas, Louisiana, Maryland, Massachusetts, Minnesota, Mississippi, Missouri, Montana, Nebraska, Nevada, New Jersey, New Mexico, New York, North Carolina, North Dakota, Oklahoma, Pennsylvania, South Carolina, South Dakota, Tennessee, Texas, Utah, Virginia, Washington, D.C., Washington and Wyoming, but not in Florida, Hawaii, Illinois, Indiana, Kentucky, Maine, Michigan, New Hampshire, Ohio, Oregon, Rhode Island, Vermont, West Virginia, or Wisconsin. Washington is the latest state to have found their first dinosaur bone, it was recovered in 2012 but was not publicly identified until May 21, 2015. Some states contain rocks of the appropriate type and age to preserve dinosaur fossils, so the list of states with known dinosaur fossils is likely to increase in the future.

Pharmacokinetics

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Pharmacokinetics 

Pharmacokinetics (from Ancient Greek pharmakon "drug" and kinetikos "moving, putting in motion"; see chemical kinetics), 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, pesticides, food additives, cosmetics, 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 completely eliminated from the body. Pharmacokinetics is the study of how an organism affects a drug, whereas pharmacodynamics (PD) is the study of how the drug affects the organism. Both together influence dosing, benefit, and adverse effects, as seen in PK/PD models.

IUPAC definition

Pharmacokinetics:

1. Process of the uptake of drugs by the body, the biotransformation they undergo, the distribution of the drugs and their metabolites in the tissues, and the elimination of the drugs and their metabolites from the body over a period of time.
2. Study of more such related processes

Overview

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 (e.g. by metabolic enzymes such as cytochrome P450 or glucuronosyltransferase enzymes), and 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.

Topics of Pharmacokinetics

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 commonly used approximations to reality; however, the complexity involved in adding parameters with that modelling approach means that monocompartmental models and above all two compartmental models are the most-frequently used. The various compartments that the model is divided into are commonly referred to as the ADME scheme (also referred to as LADME if liberation is included as a separate step from absorption):

• Liberation – the process of release of a drug from the pharmaceutical formulation. See also 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 (or biotransformation, or inactivation) – 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 also 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 fully 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 (pKa), bioavailability and solubility, absorption capacity and distribution in the organism.

The model outputs for a drug can be used in industry (for example, in calculating bioequivalence when designing generic drugs) 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.

Metrics

The following are the most commonly measured pharmacokinetic metrics: The units of the dose in the table are expressed in moles (mol) and molar (M). To express the metrics of the table in units of mass, instead of Amount of substance, simply replace 'mol' with 'g' and 'M' with 'g/dm3'. Similarly, other units in the table may be expressed in units of an equivalent dimension by scaling.

Pharmacokinetic metrics

Characteristic	Description	Symbol	Unit	Formula	Worked example value
Dose	Amount of drug administered.	${\displaystyle D}$	${\displaystyle \mathrm {mol} }$	Design parameter	500 mmol
Dosing interval	Time between drug dose administrations.	${\displaystyle \tau }$	${\displaystyle \mathrm {h} }$	Design parameter	24 h
Cmax	The peak plasma concentration of a drug after administration.	${\displaystyle C_{\text{max}}}$	${\displaystyle \mathrm {mmol/L} }$	Direct measurement	60.9 mmol/L
tmax	Time to reach Cmax.	${\displaystyle t_{\text{max}}}$	${\displaystyle \mathrm {h} }$	Direct measurement	3.9 h
Cmin	The lowest (trough) concentration that a drug reaches before the next dose is administered.	${\displaystyle C_{{\text{min}},{\text{ss}}}}$	${\displaystyle \mathrm {mmol/L} }$	Direct measurement	27.7 mmol/L
Cmean or Cavg	The mean plasma concentration of a drug over a specified interval of time.	${\displaystyle C_{{\text{mean}},{\text{ss}}}}$	${\displaystyle \mathrm {mmol/L} }$	Direct measurement	59.3 pmol/L
Volume of distribution	The apparent volume in which a drug is distributed (i.e., the parameter relating drug concentration in plasma to drug amount in the body).	${\displaystyle V_{\text{d}}}$	${\displaystyle \mathrm {L} }$	${\displaystyle {\frac {D}{C_{0}}}}$	6.0 L
Concentration	Amount of drug in a given volume of plasma.	${\displaystyle C_{0},C_{\text{ss}}}$	${\displaystyle \mathrm {mmol/L} }$	${\displaystyle {\frac {D}{V_{\text{d}}}}}$	83.3 mmol/L
Absorption half-life	The time required for 50% of a given dose of drug to be absorbed into the systemic circulation.	${\displaystyle t_{{\frac {1}{2}}a}}$	${\displaystyle \mathrm {h} }$	${\displaystyle {\frac {\ln(2)}{k_{\text{a}}}}}$	1.0 h
Absorption rate constant	The rate at which a drug enters into the body for oral and other extravascular routes.	${\displaystyle k_{\text{a}}}$	${\displaystyle \mathrm {h} ^{-1}}$	${\displaystyle {\frac {\ln(2)}{t_{{\frac {1}{2}}a}}}}$	0.693 h−1
Elimination half-‍life	The time required for the concentration of the drug to reach half of its original value.	${\displaystyle t_{{\frac {1}{2}}b}}$	${\displaystyle \mathrm {h} }$	${\displaystyle {\frac {\ln(2)}{k_{\text{e}}}}}$	12 h
Elimination rate constant	The rate at which a drug is removed from the body.	${\displaystyle k_{\text{e}}}$	${\displaystyle \mathrm {h} ^{-1}}$	${\displaystyle {\frac {\ln(2)}{t_{{\frac {1}{2}}b}}}={\frac {CL}{V_{\text{d}}}}}$	0.0578 h−1
Infusion rate	Rate of infusion required to balance elimination.	${\displaystyle k_{\text{in}}}$	${\displaystyle \mathrm {mol/h} }$	${\displaystyle C_{\text{ss}}\cdot CL}$	50 mmol/h
Area under the curve	The integral of the concentration-time curve (after a single dose or in steady state).	${\displaystyle AUC_{0-\infty }}$	${\displaystyle \mathrm {M} \cdot \mathrm {s} }$	${\displaystyle \int _{0}^{\infty }C\,\operatorname {d} t}$	1,320 mmol/L·h
		${\displaystyle AUC_{\tau ,{\text{ss}}}}$	${\displaystyle \mathrm {M} \cdot \mathrm {s} }$	${\displaystyle \int _{t}^{t+\tau }C\,\operatorname {d} t}$
Clearance	The volume of plasma cleared of the drug per unit time.	${\displaystyle CL}$	${\displaystyle \mathrm {m} ^{3}/\mathrm {s} }$	${\displaystyle V_{\text{d}}\cdot k_{\text{e}}={\frac {D}{AUC}}}$	0.38 L/h
Bioavailability	The systemically available fraction of a drug.	${\displaystyle f}$	Unitless	${\displaystyle {\frac {AUC_{\text{po}}\cdot D_{\text{iv}}}{AUC_{\text{iv}}\cdot D_{\text{po}}}}}$	0.8
Fluctuation	Peak–trough fluctuation within one dosing interval at steady state.	${\displaystyle \%PTF}$	${\displaystyle \%}$	${\displaystyle {\frac {C_{{\text{max}},{\text{ss}}}-C_{{\text{min}},{\text{ss}}}}{C_{{\text{av}},{\text{ss}}}}}\cdot 100\%}$ where ${\displaystyle C_{{\text{av}},{\text{ss}}}={\frac {1}{\tau }}AUC_{\tau ,{\text{ss}}}}$	41.8%

In pharmacokinetics, steady state refers to the situation where the overall intake of a drug is fairly in dynamic equilibrium with its elimination. In practice, it is generally considered that steady state is reached when a time of 3 to 5 times the half-life for a drug after regular dosing is started.

Pharmacokinetic models

The time course of drug plasma concentrations over 96 hours following oral administrations every 24 hours. Note that in steady state and in linear pharmacokinetics AUCτ=AUC∞. Steady state is reached after about 5 × 12 = 60 hours. The 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 often more versatile in that they do not assume any specific compartmental model and produce accurate results also 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 (first order kinetics).

However, these models do not always truly 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 (such as the brain tissue) that present a real barrier to the distribution of drugs, that can be breached with greater or lesser ease depending on the drug's characteristics. If these relative conditions for the different tissue types are considered along with the rate of elimination, the organism can be considered to be acting like two compartments: one that we can call the central compartment that has a more rapid distribution, comprising organs and systems with a well-developed blood supply; and a peripheral compartment made up of organs with a lower blood flow. Other tissues, such as the brain, can occupy a variable position depending on a drug's ability to cross the barrier that separates the organ from the blood supply.

This two compartment model will vary depending on which compartment elimination occurs in. The most common situation is that elimination occurs in the central compartment as the liver and kidneys are organs with a good blood supply. However, in some situations it may be that elimination occurs in the peripheral compartment or even in both. This can mean that there are three possible variations in the two compartment model, which still do not cover all possibilities.

This model may not be applicable in situations where some of the enzymes responsible for metabolizing the drug become saturated, or where an active elimination mechanism is present that is independent of the drug's plasma concentration. In the real world each tissue will have its own distribution characteristics and none of them will be strictly linear. If we label the drug's volume of distribution within the organism Vd_F and its volume of distribution in a tissue Vd_T the former will be described by an equation that takes into account all the tissues that act in different ways, that is:

${\displaystyle Vd_{F}=Vd_{T1}+Vd_{T2}+Vd_{T3}+\cdots +Vd_{Tn}\,}$

This represents the multi-compartment model with a number of curves that express complicated equations in order to obtain an overall curve. A number of computer programs have been developed to plot these equations. However complicated and precise this model may be, it still does not truly represent reality despite the effort involved in obtaining various distribution values for a drug. This is because the concept of distribution volume is a relative concept that is not a true reflection of reality. The choice of model therefore comes down to deciding which one offers the lowest margin of error for the drug involved.

Graph representing the monocompartmental action model.

Noncompartmental analysis

Noncompartmental PK analysis is highly dependent on estimation of total drug exposure. Total drug exposure is most often estimated by area under the curve (AUC) methods, with the trapezoidal rule (numerical integration) the most common method. Due to the dependence on the length of x in the trapezoidal rule, the area estimation is highly dependent on the blood/plasma sampling schedule. That is, the closer time points are, the closer the trapezoids reflect the actual shape of the concentration-time curve. The number of time points available in order to perform a successful NCA analysis should be enough to cover the absorption, distribution and elimination phase to accurately characterize the drug. Beyond AUC exposure measures, parameters such as Cmax (maximum concentration), Tmax(time at maximum concentration), CL and Vd can also be reported using NCA methods.

Compartmental analysis

Compartmental PK analysis uses kinetic models to describe and predict the concentration-time curve. PK compartmental models are often similar to kinetic models used in other scientific disciplines such as chemical kinetics and thermodynamics. The advantage of compartmental over some noncompartmental analyses is the ability to predict the concentration at any time. The disadvantage is the difficulty in developing and validating the proper model. Compartment-free modelling based on curve stripping does not suffer this limitation. The simplest PK compartmental model is the one-compartmental PK model with IV bolus administration and first-order elimination. The most complex PK models (called PBPK models) rely on the use of physiological information to ease development and validation.

Single-compartment model

Linear pharmacokinetics is so-called because the graph of the relationship between the various factors involved (dose, blood plasma concentrations, elimination, etc.) gives a straight line or an approximation to one. For drugs to be effective they need to be able to move rapidly from blood plasma to other body fluids and tissues.

The change in concentration over time can be expressed as ${\displaystyle C=C_{\text{initial}}\times e^{-k_{\text{el}}\times t}}$

Multi-compartmental models

Graphs for absorption and elimination for a non-linear pharmacokinetic model.

The graph for the non-linear relationship between the various factors is represented by a curve; the relationships between the factors can then be found by calculating the dimensions of different areas under the curve. The models used in non-linear pharmacokinetics are largely based on Michaelis–Menten kinetics. A reaction's factors of non-linearity include the following:

• Multiphasic absorption: Drugs injected intravenously are removed from the plasma through two primary mechanisms: (1) Distribution to body tissues and (2) metabolism + excretion of the drugs. The resulting decrease of the drug's plasma concentration follows a biphasic pattern (see figure).
  

• Plasma drug concentration vs time after an IV dose
  • Alpha phase: An initial phase of rapid decrease in plasma concentration. The decrease is primarily attributed to drug distribution from the central compartment (circulation) into the peripheral compartments (body tissues). This phase ends when a pseudo-equilibrium of drug concentration is established between the central and peripheral compartments.
  • Beta phase: A phase of gradual decrease in plasma concentration after the alpha phase. The decrease is primarily attributed to drug elimination, that is, metabolism and excretion.
  • Additional phases (gamma, delta, etc.) are sometimes seen.
• A drug's characteristics make a clear distinction between tissues with high and low blood flow.
• Enzymatic saturation: When the dose of a drug whose elimination depends on biotransformation is increased above a certain threshold the enzymes responsible for its metabolism become saturated. The drug's plasma concentration will then increase disproportionately and its elimination will no longer be constant.
• Induction or enzymatic inhibition: Some drugs have the capacity to inhibit or stimulate their own metabolism, in negative or positive feedback reactions. As occurs with fluvoxamine, fluoxetine and phenytoin. As larger doses of these pharmaceuticals are administered the plasma concentrations of the unmetabolized drug increases and the elimination half-life increases. It is therefore necessary to adjust the dose or other treatment parameters when a high dosage is required.
• The kidneys can also establish active elimination mechanisms for some drugs, independent of plasma concentrations.

It can therefore be seen that non-linearity can occur because of reasons that affect the entire pharmacokinetic sequence: absorption, distribution, metabolism and elimination.

Bioavailability

Different forms of tablets, which will have different pharmacokinetic behaviours after their administration.

 

Main article: Bioavailability

At a practical level, a drug's bioavailability can be defined as the proportion of the drug that reaches its site of action. From this perspective the intravenous administration of a drug provides the greatest possible bioavailability, and this method is considered to yield a bioavailability of 1 (or 100%). Bioavailability of other delivery methods is compared with that of intravenous injection (absolute bioavailability) or to a standard value related to other delivery methods in a particular study (relative bioavailability).

${\displaystyle B_{A}={\frac {[ABC]_{P}\cdot D_{IV}}{[ABC]_{IV}\cdot D_{P}}}}$

${\displaystyle {\mathit {B}}_{R}={\frac {[ABC]_{A}\cdot {\text{dose}}_{B}}{[ABC]_{B}\cdot {\text{dose}}_{A}}}}$

Once a drug's bioavailability has been established it is possible to calculate the changes that need to be made to its dosage in order to reach the required blood plasma levels. Bioavailability is, therefore, a mathematical factor for each individual drug that influences the administered dose. It is possible to calculate the amount of a drug in the blood plasma that has a real potential to bring about its effect using the formula:

${\displaystyle De=B\cdot Da\,}$

where De is the effective dose, B bioavailability and Da the administered dose.

Therefore, if a drug has a bioavailability of 0.8 (or 80%) and it is administered in a dose of 100 mg, the equation will demonstrate the following:

De = 0.8 × 100 mg = 80 mg

That is the 100 mg administered represents a blood plasma concentration of 80 mg that has the capacity to have a pharmaceutical effect.

This concept depends on a series of factors inherent to each drug, such as:

• Pharmaceutical form
• Chemical form
• Route of administration
• Stability
• Metabolism

These concepts, which are discussed in detail in their respective titled articles, can be mathematically quantified and integrated to obtain an overall mathematical equation:

${\displaystyle De=Q\cdot Da\cdot B\,}$

where Q is the drug's purity.

${\displaystyle Va={\frac {Da\cdot B\cdot Q}{\tau }}}$

where ${\displaystyle Va}$ is the drug's rate of administration and ${\displaystyle \tau }$ is the rate at which the absorbed drug reaches the circulatory system.

Finally, using the Henderson-Hasselbalch equation, and knowing the drug's ${\displaystyle pKa\,}$ (pH at which there is an equilibrium between its ionized and non ionized molecules), it is possible to calculate the non ionized concentration of the drug and therefore the concentration that will be subject to absorption:

${\displaystyle \mathrm {pH} =\mathrm {pKa} +\log {\frac {B}{A}}}$

When two drugs have the same bioavailability, they are said to be biological equivalents or bioequivalents. This concept of bioequivalence is important because it is currently used as a yardstick in the authorization of generic drugs in many countries.

LADME

Main article: ADME

A number of phases occur once the drug enters into contact with the organism, these are described using the acronym LADME:

• Liberation of the active substance from the delivery system,
• Absorption of the active substance by the organism,
• Distribution through the blood plasma and different body tissues,
• Metabolism that is inactivation of the xenobiotic substance, and finally
• Excretion or elimination of the substance or the products of its metabolism.

Some textbooks combine the first two phases as the drug is often administered in an active form, which means that there is no liberation phase. Others include a phase that combines distribution, metabolism and excretion into a disposition phase. Other authors include the drug's toxicological aspect in what is known as ADME-Tox or ADMET.

Each of the phases is subject to physico-chemical interactions between a drug and an organism, which can be expressed mathematically. Pharmacokinetics is therefore based on mathematical equations that allow the prediction of a drug's behavior and which place great emphasis on the relationships between drug plasma concentrations and the time elapsed since the drug's administration.

Analysis

Bioanalytical methods

Bioanalytical methods are necessary to construct a concentration-time profile. Chemical techniques are employed to measure the concentration of drugs in biological matrix, most often plasma. Proper bioanalytical methods should be selective and sensitive. For example, microscale thermophoresis can be used to quantify how the biological matrix/liquid affects the affinity of a drug to its target.

Mass spectrometry

Pharmacokinetics is often studied using mass spectrometry because of the complex nature of the matrix (often plasma or urine) and the need for high sensitivity to observe concentrations after a low dose and a long time period. The most common instrumentation used in this application is LC-MS with a triple quadrupole mass spectrometer. Tandem mass spectrometry is usually employed for added specificity. Standard curves and internal standards are used for quantitation of usually a single pharmaceutical in the samples. The samples represent different time points as a pharmaceutical is administered and then metabolized or cleared from the body. Blank samples taken before administration are important in determining background and ensuring data integrity with such complex sample matrices. Much attention is paid to the linearity of the standard curve; however it is common to use curve fitting with more complex functions such as quadratics since the response of most mass spectrometers is not linear across large concentration ranges.

There is currently considerable interest in the use of very high sensitivity mass spectrometry for microdosing studies, which are seen as a promising alternative to animal experimentation. Recent studies show that Secondary electrospray ionization (SESI-MS) can be used in drug monitoring, presenting the advantage of avoiding animal sacrifice.

Population pharmacokinetics

Population pharmacokinetics is the study of the sources and correlates of variability in drug concentrations among individuals who are the target patient population receiving clinically relevant doses of a drug of interest. Certain patient demographic, pathophysiological, and therapeutical features, such as body weight, excretory and metabolic functions, and the presence of other therapies, can regularly alter dose-concentration relationships and can explain variability in exposures. For example, steady-state concentrations of drugs eliminated mostly by the kidney are usually greater in patients suffering from kidney failure than they are in patients with normal kidney function receiving the same drug dosage. Population pharmacokinetics seeks to identify the measurable pathophysiologic factors and explain sources of variability that cause changes in the dose-concentration relationship and the extent of these changes so that, if such changes are associated with clinically relevant and significant shifts in exposures that impact the therapeutic index, dosage can be appropriately modified. An advantage of population pharmacokinetic modelling is its ability to analyse sparse data sets (sometimes only one concentration measurement per patient is available).

Clinical pharmacokinetics

Drugs where pharmacokinetic monitoring is recommended

Antiepileptic medication	Cardioactive medication	Immunosuppressor medication	Antibiotic medication
Phenytoin Carbamazepine Valproic acid Lamotrigine Ethosuximide Phenobarbital Primidone	Digoxin Lidocaine	Ciclosporin Tacrolimus Sirolimus Everolimus Mycophenolate	Gentamicin Tobramycin Amikacin Vancomycin
Bronchodilator medication	Cytostatic medication	Antiviral (HIV) medication	Coagulation factors
Theophylline	Methotrexate 5-Fluorouracil Irinotecan	+ Efavirenz Tenofovir Ritonavir	Factor VIII, Factor IX, Factor VIIa, Factor XI

Clinical pharmacokinetics (arising from the clinical use of population pharmacokinetics) is the direct application to a therapeutic situation of knowledge regarding a drug's pharmacokinetics and the characteristics of a population that a patient belongs to (or can be ascribed to).

An example is the relaunch of the use of ciclosporin as an immunosuppressor to facilitate organ transplant. The drug's therapeutic properties were initially demonstrated, but it was almost never used after it was found to cause nephrotoxicity in a number of patients. However, it was then realized that it was possible to individualize a patient's dose of ciclosporin by analysing the patients plasmatic concentrations (pharmacokinetic monitoring). This practice has allowed this drug to be used again and has facilitated a great number of organ transplants.

Clinical monitoring is usually carried out by determination of plasma concentrations as this data is usually the easiest to obtain and the most reliable. The main reasons for determining a drug's plasma concentration include:

• Narrow therapeutic range (difference between toxic and therapeutic concentrations)
• High toxicity
• High risk to life.

Ecotoxicology

Ecotoxicology is the branch of science that deals with the nature, effects, and interactions of substances that are harmful to the environment.