ADME
Encyclopedia
ADME is an acronym in pharmacokinetics
and pharmacology
for absorption
, distribution
, metabolism
, and excretion
, and describes the disposition of a pharmaceutical compound
within an organism
. The four criteria all influence the drug levels and kinetics of drug exposure to the tissues and hence influence the performance and pharmacological activity of the compound as a drug
.
surfaces like the digestive tract (intestinal absorption) - before being taken up by the target cells. Factors such as poor compound solubility, gastric emptying time, intestinal transit time, chemical instability in the stomach, and inability to permeate the intestinal wall can all reduce the extent to which a drug is absorbed after oral administration. Absorption critically determines the compound's bioavailability
. Drugs that absorb poorly when taken orally must be administered
in some less desirable way, like intravenously
or by inhalation
(e.g. zanamivir).
Distribution is defined as the reversible transfer of a drug between one compartment to another. Some factors affecting drug distribution include regional blood flow rates, molecular size, polarity and binding to serum proteins, forming a complex. Distribution can be a serious problem at some natural barriers like the blood-brain barrier
.
enzymes, termed cytochrome P450 enzymes. As metabolism occurs, the initial (parent) compound is converted to new compounds called metabolite
s. When metabolites are pharmacologically inert, metabolism deactivates the administered dose of parent drug and this usually reduces the effects on the body. Metabolites may also be pharmacologically active, sometimes more so than the parent drug.
s need to be removed from the body via excretion
, usually through the kidney
s (urine) or in the feces. Unless excretion is complete, accumulation of foreign substances can adversely affect normal metabolism.
There are three sites where drug excretion occurs. The kidney is the most important site and it is where products are excreted through urine. Biliary excretion or fecal excretion is the process that initiates in the liver and passes through to the gut until the products are finally excreted along with waste products or feces. The last method of excretion is through the lungs e.g. anesthetic gases.
Excretion of drugs by the kidney involves 3 main mechanisms:
of the compound is taken into account (ADME-Tox or ADMET). When the Liberation of the substance (from protective coating, or other excipient
s) is considered, we speak of LADME.
Computational chemists
try to predict the ADME-Tox qualities of compounds through methods like QSPR or QSAR
.
The route of administration
critically influences ADME.
Andrew mtewa
Pharmacokinetics
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...
and pharmacology
Pharmacology
Pharmacology is the branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function...
for absorption
Absorption (Pharmacokinetics)
In pharmacology , absorption is the movement of a drug into the bloodstream.Absorption involves several phases...
, distribution
Distribution (pharmacology)
Distribution in pharmacology is a branch of pharmacokinetics which describes the reversible transfer of drug from one location to another within the body....
, metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
, and excretion
Excretion
Excretion is the process by which waste products of metabolism and other non-useful materials are eliminated from an organism. This is primarily carried out by the lungs, kidneys and skin. This is in contrast with secretion, where the substance may have specific tasks after leaving the cell...
, and describes the disposition of a pharmaceutical compound
Chemical compound
A chemical compound is a pure chemical substance consisting of two or more different chemical elements that can be separated into simpler substances by chemical reactions. Chemical compounds have a unique and defined chemical structure; they consist of a fixed ratio of atoms that are held together...
within an organism
Organism
In biology, an organism is any contiguous living system . In at least some form, all organisms are capable of response to stimuli, reproduction, growth and development, and maintenance of homoeostasis as a stable whole.An organism may either be unicellular or, as in the case of humans, comprise...
. The four criteria all influence the drug levels and kinetics of drug exposure to the tissues and hence influence the performance and pharmacological activity of the compound as a drug
Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...
.
Absorption/Administration
For a compound to reach a tissue, it usually must be taken into the bloodstream - often via mucousMucus
In vertebrates, mucus is a slippery secretion produced by, and covering, mucous membranes. Mucous fluid is typically produced from mucous cells found in mucous glands. Mucous cells secrete products that are rich in glycoproteins and water. Mucous fluid may also originate from mixed glands, which...
surfaces like the digestive tract (intestinal absorption) - before being taken up by the target cells. Factors such as poor compound solubility, gastric emptying time, intestinal transit time, chemical instability in the stomach, and inability to permeate the intestinal wall can all reduce the extent to which a drug is absorbed after oral administration. Absorption critically determines the compound's bioavailability
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
. Drugs that absorb poorly when taken orally must be administered
Route of administration
A route of administration in pharmacology and toxicology is the path by which a drug, fluid, poison, or other substance is taken into the body.-Classification:Routes of administration are usually classified by application location...
in some less desirable way, like intravenously
Intravenous therapy
Intravenous therapy or IV therapy is the infusion of liquid substances directly into a vein. The word intravenous simply means "within a vein". Therapies administered intravenously are often called specialty pharmaceuticals...
or by inhalation
Inhalation
Inhalation is the movement of air from the external environment, through the air ways, and into the alveoli....
(e.g. zanamivir).
Distribution
The compound needs to be carried to its effector site, most often via the bloodstream. From there, the compound may distribute into tissues and organs, usually to differing extents. After entry into the systemic circulation, either by intravascular injection or by absorption from any of the various extracellular sites, the drug is subjected to numerous distribution processes that tend to lower its plasma concentration.Distribution is defined as the reversible transfer of a drug between one compartment to another. Some factors affecting drug distribution include regional blood flow rates, molecular size, polarity and binding to serum proteins, forming a complex. Distribution can be a serious problem at some natural barriers like the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
.
Metabolism
Compounds begin to break down as soon as they enter the body. The majority of small-molecule drug metabolism is carried out in the liver by redoxRedox
Redox reactions describe all chemical reactions in which atoms have their oxidation state changed....
enzymes, termed cytochrome P450 enzymes. As metabolism occurs, the initial (parent) compound is converted to new compounds called metabolite
Metabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...
s. When metabolites are pharmacologically inert, metabolism deactivates the administered dose of parent drug and this usually reduces the effects on the body. Metabolites may also be pharmacologically active, sometimes more so than the parent drug.
Excretion/Elimination
Compounds and their metaboliteMetabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...
s need to be removed from the body via excretion
Excretion
Excretion is the process by which waste products of metabolism and other non-useful materials are eliminated from an organism. This is primarily carried out by the lungs, kidneys and skin. This is in contrast with secretion, where the substance may have specific tasks after leaving the cell...
, usually through the kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
s (urine) or in the feces. Unless excretion is complete, accumulation of foreign substances can adversely affect normal metabolism.
There are three sites where drug excretion occurs. The kidney is the most important site and it is where products are excreted through urine. Biliary excretion or fecal excretion is the process that initiates in the liver and passes through to the gut until the products are finally excreted along with waste products or feces. The last method of excretion is through the lungs e.g. anesthetic gases.
Excretion of drugs by the kidney involves 3 main mechanisms:
- Glomerular filtration of unbound drug.
- Active secretion of (free & protein-bound) drug by transporters e.g. anions such as urate, penicillinPenicillinPenicillin is a group of antibiotics derived from Penicillium fungi. They include penicillin G, procaine penicillin, benzathine penicillin, and penicillin V....
, glucuronideGlucuronideA glucuronide, also known as glucuronoside, is any substance produced by linking glucuronic acid to another substance via a glycosidic bond...
, sulfateSulfateIn inorganic chemistry, a sulfate is a salt of sulfuric acid.-Chemical properties:...
conjugates) or cations such as cholineCholineCholine is a water-soluble essential nutrient. It is usually grouped within the B-complex vitamins. Choline generally refers to the various quaternary ammonium salts containing the N,N,N-trimethylethanolammonium cation....
, histamineHistamineHistamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by...
. - Filtrate 100-fold concentrated in tubules for a favorable concentration gradient so that it may be reabsorbed by passive diffusion and passed out through the urine.
Toxicity
Sometimes, the potential or real toxicityToxicity
Toxicity is the degree to which a substance can damage a living or non-living organisms. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a substructure of the organism, such as a cell or an organ , such as the liver...
of the compound is taken into account (ADME-Tox or ADMET). When the Liberation of the substance (from protective coating, or other excipient
Excipient
An excipient is generally a pharmacologically inactive substance used as a carrier for the active ingredients of a medication. In many cases, an "active" substance may not be easily administered and absorbed by the human body; in such cases the substance in question may be dissolved into or...
s) is considered, we speak of LADME.
Computational chemists
Computational chemistry
Computational chemistry is a branch of chemistry that uses principles of computer science to assist in solving chemical problems. It uses the results of theoretical chemistry, incorporated into efficient computer programs, to calculate the structures and properties of molecules and solids...
try to predict the ADME-Tox qualities of compounds through methods like QSPR or QSAR
Quantitative structure-activity relationship
Quantitative structure–activity relationship or QSPR is the process by which chemical structure is quantitatively correlated with a well defined process, such as biological activity or chemical reactivity.For example, biological activity can be expressed quantitatively as the concentration of a...
.
The route of administration
Route of administration
A route of administration in pharmacology and toxicology is the path by which a drug, fluid, poison, or other substance is taken into the body.-Classification:Routes of administration are usually classified by application location...
critically influences ADME.
Lethal concentration
Lethal concentration of a drug can be determined in the laboratory by the brine shrimp susceptibility test. culture the brine shrimp eggs and then the larvae (nauplii) hatch, administer the drug extracts. Plot graph of mortality against concentration of the drug extracts to find LC50 as concentration that kills 50% of the nauplii by interporlation, or any other concentratuion you desire.Acute toxicity
Administer drug extracts to living animals like rats at a clinical level. Observe toxicological results physically or psychologically. later,conduct a full blood test of the animals and obesrve each part of the animal as response to the drug administered.Andrew mtewa
See also
- BioavailabilityBioavailabilityIn pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
- Caco-2Caco-2The Caco-2 cell line is a continuous line of heterogeneous human epithelial colorectal adenocarcinoma cells, developed by the Sloan-Kettering Institute for Cancer Research through research conducted by Dr...
- CheminformaticsCheminformaticsCheminformatics is the use of computer and informational techniques, applied to a range of problems in the field of chemistry. These in silico techniques are used in pharmaceutical companies in the process of drug discovery...
- Combinatorial chemistryCombinatorial chemistryCombinatorial chemistry involves the rapid synthesis or the computer simulation of a large number of different but structurally related molecules or materials...
- Lipinski's Rule of FiveLipinski's Rule of FiveLipinski's Rule of Five is a rule of thumb to evaluate druglikeness or determine if a chemical compound with a certain pharmacological or biological activity has properties that would make it a likely orally active drug in humans. The rule was formulated by Christopher A...
- PAMPAPAMPAPAMPA is a method which determines the permeability of substances from a donor compartment, through a lipid-infused artificial membrane into an acceptor compartment...
((parallel artificial membrane permeability assay)) - PharmacokineticsPharmacokineticsPharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...
- PharmacologyPharmacologyPharmacology is the branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function...
- SerumBlood plasmaBlood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
- Simcyp SimulatorSimcyp SimulatorThe Simcyp population-based ADME simulator is a modelling and simulation platform used by the pharmaceutical industry in drug discovery and development...
- Simulations PlusSimulations PlusSimulations Plus, Inc. develops absorption, distribution, metabolism, excretion, and toxicity modeling and simulation software for the pharmaceutical and biotechnology industries...
- SolubilitySolubilitySolubility is the property of a solid, liquid, or gaseous chemical substance called solute to dissolve in a solid, liquid, or gaseous solvent to form a homogeneous solution of the solute in the solvent. The solubility of a substance fundamentally depends on the used solvent as well as on...
External links
- Everything You Needed to Know About ADME, but Were too Afraid to Ask
- Open Access ADME/PK Database
- OCHEM.eu - Free online database of ADME measurements intergrated with a QSAR modeling environment
- http://www.netsci.org/Science/Special/feature06.html The Emerging Role of A.D.M.E. in Optimizing Drug Discovery and Design]