ADME is an acronym used in pharmacology. It stands for Absorption, Distribution, Metabolism, and Excretion. In short, these are the processes that take place in our body in the context of foreign substances, including drugs. It is how drugs are absorbed, transported around our body, metabolized, and excreted that affects whether a drug is effective (reaches its destination) and safe (does not cause side effects).
Metabolomics-Introduction, metabolism, intermediary metabolism, metabolic pathways, metabolites, metabolome, metabolic turnover, techniques used in metabolomics, metabolite profiling methods, data analysis, metabolomic resources, role of metabolomics in system biology.
The document discusses semipermeability of cell membranes. It explains that the cell membrane is semipermeable and can control what molecules move in and out of the cell. There are two ways molecules can move across the membrane - passive diffusion, which does not use energy, and active transport, which uses energy. Diffusion and osmosis are described as passive mechanisms of movement across the membrane. Tonicity and its effect on cell size is also discussed.
Introduction to Medicinal Chemistry, History and development of medicinal chemistry, Physicochemical properties in relation to biological action Ionization, Solubility, Partition Coefficient, Hydrogen bonding, Protein binding, Chelation, Bioisosterism, Optical and Geometrical isomerism, Drug metabolism Drug metabolism principles- Phase I and Phase II. Factors affecting drug metabolism including stereo chemical aspects
1. The document discusses the processes involved in a drug molecule traveling through the human body from administration to reaching its target site, known as pharmacokinetics.
2. Pharmacokinetics involves absorption of the drug into systemic circulation, distribution of the drug via blood plasma to tissues and organs, and elimination of the drug from the body through biotransformation or excretion.
3. For a drug to have an effect, it must reach the biophase, or site of action, at an appropriate concentration by passing through biological barriers in the body via processes like passive diffusion, carrier-mediated transport, vesicular transport, or paracellular transport between cells.
Pharmacokinetics is the quantitative study of how the body affects a drug after administration through processes of absorption, distribution, metabolism, and excretion. Absorption involves a drug entering systemic circulation through various routes and is affected by properties of the drug and biological membranes. Distribution involves a drug passing through body compartments depending on its physicochemical properties. Metabolism chemically alters drugs in the liver to make them more excretable, while excretion removes drugs and metabolites through the kidneys, lungs, bile, intestines, skin, and other routes.
Cells require transport mechanisms to move substances into and out of them. There are different mechanisms including diffusion, osmosis, and active transport. The cell membrane is a selectively permeable barrier composed of a phospholipid bilayer and embedded proteins. Transport proteins such as carrier and channel proteins facilitate the passage of molecules across the membrane through diffusion or active transport powered by ATP.
The document discusses toxicokinetics, which is the study of how chemicals move through the body via absorption, distribution, metabolism, and excretion. It specifically addresses:
- Toxicokinetics examines these four processes to understand what the body does to a toxicant.
- Radio labeled doses of chemicals can be used to track their fate throughout tissues and elimination from the body, but may not show the amounts of parent chemicals versus metabolites.
- Absorption of chemicals can occur via passive diffusion, active transport, or facilitated transport across membranes depending on properties like solubility and size. Factors like pH, concentration, food, and gastrointestinal factors influence absorption.
This document provides an introduction to pharmacology concepts. It discusses what drugs are and how they work in the body. It covers absorption, distribution, metabolism, and excretion of drugs. Absorption involves passive diffusion, carrier-mediated transport, and endocytosis. Distribution depends on blood flow, protein binding, and accumulation in tissues. Metabolism occurs mainly in the liver through phase I and phase II reactions. Excretion involves renal and hepatic systems with water-soluble drugs or metabolites excreted in urine or bile.
Metabolomics-Introduction, metabolism, intermediary metabolism, metabolic pathways, metabolites, metabolome, metabolic turnover, techniques used in metabolomics, metabolite profiling methods, data analysis, metabolomic resources, role of metabolomics in system biology.
The document discusses semipermeability of cell membranes. It explains that the cell membrane is semipermeable and can control what molecules move in and out of the cell. There are two ways molecules can move across the membrane - passive diffusion, which does not use energy, and active transport, which uses energy. Diffusion and osmosis are described as passive mechanisms of movement across the membrane. Tonicity and its effect on cell size is also discussed.
Introduction to Medicinal Chemistry, History and development of medicinal chemistry, Physicochemical properties in relation to biological action Ionization, Solubility, Partition Coefficient, Hydrogen bonding, Protein binding, Chelation, Bioisosterism, Optical and Geometrical isomerism, Drug metabolism Drug metabolism principles- Phase I and Phase II. Factors affecting drug metabolism including stereo chemical aspects
1. The document discusses the processes involved in a drug molecule traveling through the human body from administration to reaching its target site, known as pharmacokinetics.
2. Pharmacokinetics involves absorption of the drug into systemic circulation, distribution of the drug via blood plasma to tissues and organs, and elimination of the drug from the body through biotransformation or excretion.
3. For a drug to have an effect, it must reach the biophase, or site of action, at an appropriate concentration by passing through biological barriers in the body via processes like passive diffusion, carrier-mediated transport, vesicular transport, or paracellular transport between cells.
Pharmacokinetics is the quantitative study of how the body affects a drug after administration through processes of absorption, distribution, metabolism, and excretion. Absorption involves a drug entering systemic circulation through various routes and is affected by properties of the drug and biological membranes. Distribution involves a drug passing through body compartments depending on its physicochemical properties. Metabolism chemically alters drugs in the liver to make them more excretable, while excretion removes drugs and metabolites through the kidneys, lungs, bile, intestines, skin, and other routes.
Cells require transport mechanisms to move substances into and out of them. There are different mechanisms including diffusion, osmosis, and active transport. The cell membrane is a selectively permeable barrier composed of a phospholipid bilayer and embedded proteins. Transport proteins such as carrier and channel proteins facilitate the passage of molecules across the membrane through diffusion or active transport powered by ATP.
The document discusses toxicokinetics, which is the study of how chemicals move through the body via absorption, distribution, metabolism, and excretion. It specifically addresses:
- Toxicokinetics examines these four processes to understand what the body does to a toxicant.
- Radio labeled doses of chemicals can be used to track their fate throughout tissues and elimination from the body, but may not show the amounts of parent chemicals versus metabolites.
- Absorption of chemicals can occur via passive diffusion, active transport, or facilitated transport across membranes depending on properties like solubility and size. Factors like pH, concentration, food, and gastrointestinal factors influence absorption.
This document provides an introduction to pharmacology concepts. It discusses what drugs are and how they work in the body. It covers absorption, distribution, metabolism, and excretion of drugs. Absorption involves passive diffusion, carrier-mediated transport, and endocytosis. Distribution depends on blood flow, protein binding, and accumulation in tissues. Metabolism occurs mainly in the liver through phase I and phase II reactions. Excretion involves renal and hepatic systems with water-soluble drugs or metabolites excreted in urine or bile.
In vitro screening for evaluation of drugs ADMET propertiesdilip kumar tampula
The document discusses pre-clinical in vitro screening techniques used to evaluate drugs' absorption, distribution, metabolism, excretion and toxicity (ADMET) properties early in the drug discovery process. It describes assays for various ADMET properties including partition coefficient, aqueous solubility, metabolic stability, plasma protein binding, and toxicity. The assays allow rapid evaluation of compounds with low amounts of material and help identify those with favorable pharmacokinetic and safety profiles to progress in development. The goal is to incorporate ADMET screening earlier to simultaneously optimize all drug properties.
This document provides an overview of biochemistry and pharmacology concepts. It discusses drug absorption, distribution, and excretion. It describes how drugs pass through cell membranes via filtration or active/passive transport. It also explains how drugs bind to plasma proteins and are metabolized in the liver and excreted by the kidneys or bile. The document then summarizes the mechanisms of action of antibiotics and antivirals, such as by inhibiting bacterial cell wall synthesis, protein synthesis, or viral DNA replication.
This document discusses various in vitro, in vivo, and in situ methods used to study drug absorption. It describes several in vitro techniques like partition coefficient studies, artificial membrane models, and cell culture models. It also explains various in vivo methods like direct blood/urine sampling and indirect pharmacological response studies in animals. Finally, it covers in situ techniques like intestinal perfusion that better simulate in vivo conditions compared to in vitro models. The document provides detailed descriptions of specific methods like the everted sac technique, diffusion cell method, and stomach perfusion studies in rats.
The plasma membrane surrounds cells and organelles, protecting the interior while regulating what passes in and out. It is a selectively permeable lipid bilayer containing proteins. The fluid mosaic model describes its structure as lipids and proteins moving freely within. Membranes are composed mainly of phospholipids, cholesterol, and glycolipids, with integral and peripheral proteins embedded. Transport across membranes includes passive diffusion, facilitated diffusion using carrier proteins, and active transport using ATP. Receptors on the surface receive signals from outside the cell.
Rational drug design begins by identifying a biological target implicated in disease. Drugs are then designed to modulate this target's activity in order to treat the disease. For a target to be suitable, there must be evidence it is disease-relevant and capable of binding small molecules. Once identified, the target is cloned, expressed, and purified. This allows high-throughput screening of chemical libraries to identify candidates that modify the target. Successful candidates should have properties predicting oral availability and low toxicity. Prodrugs and combinatorial chemistry are approaches that can improve drug properties and efficiency of discovery.
Toxicokinetics is the study of how the body processes toxic materials through absorption, distribution, metabolism and excretion (ADME). Absorption involves passage of toxicants across biological membranes, mainly through simple diffusion or specialized transport mechanisms. Distribution of toxicants through the body is determined by volume of distribution. Metabolism transforms toxicants into more water-soluble compounds through phase I (oxidation, reduction, hydrolysis) and phase II (conjugation) reactions. Excreted routes include renal excretion through urine and extra-renal excretion through bile, lungs, mammary glands and other secretions, terminating the toxicological effects.
This document discusses drug excretion and elimination from the body. It covers the major organs and processes involved, including the kidneys, lungs, bile/intestinal systems. Kidneys are the primary route of elimination for water-soluble drugs through glomerular filtration, tubular secretion, and reabsorption. Other topics covered include enterohepatic recirculation, factors influencing renal excretion, first vs zero order elimination kinetics, half-life, clearance, volume of distribution, and factors necessary for therapeutic drug monitoring.
The document discusses the disposition of chemicals in the body, including absorption, distribution, metabolism and excretion. It covers various factors that influence these processes such as lipid solubility, plasma protein binding, organ blood flow and enzyme activity. The kinetics of chemical elimination from the body is also described, particularly first-order elimination kinetics and the relationship between half-life, volume of distribution and clearance.
The document discusses the disposition of chemicals in the body, including absorption, distribution, metabolism and excretion. It covers various routes of exposure like oral, dermal and inhalation. Key concepts covered are factors affecting absorption, distribution between tissues and body compartments, biotransformation in the liver and excretion through kidneys, bile and other routes. The kinetics of chemical elimination from the body via first-order processes is also summarized.
This document discusses factors that affect oral drug absorption. It describes three main categories of factors: physiological, physical-chemical, and formulation factors. Under physiological factors, it discusses membrane physiology, how drugs pass membranes through different transport mechanisms like passive diffusion and active transport, and gastrointestinal physiology. It provides details on the anatomy and environments of different parts of the GI tract and how they impact drug absorption. It also discusses gastric emptying time and how it affects drug absorption.
This document provides an introduction to pharmacology and toxicology. It discusses the principles of how drugs interact with receptors in the body, including agonist and antagonist drug interactions. It also covers the pharmacokinetic principles of how drugs are absorbed, distributed, and eliminated from the body. This involves processes like permeation through aqueous and lipid barriers, as well as special carriers and pumps that facilitate drug transport. The goal is for drugs to safely reach their intended site of action and then be eliminated from the body.
Pharmacokinetics is the study of how the body affects drugs over time through absorption, distribution, metabolism, and excretion. Drugs move into, within, and out of the body through various transport mechanisms like passive diffusion, facilitated diffusion, and active transport. Factors like plasma protein binding, organ function, and route of administration influence a drug's absorption, distribution to tissues, metabolism by the liver, and excretion by the kidneys, lungs, bile, sweat, saliva or breast milk. Understanding these pharmacokinetic principles is important for predicting how drugs will behave in the body.
1. The major pathways for elimination of protein therapeutics are proteolysis and metabolism, with molecular weight being a major determinant of the specific elimination mechanisms.
2. Smaller proteins and peptides are filtered by the kidneys and undergo proteolysis, while larger proteins are taken up by the liver via receptor-mediated endocytosis and degraded in lysosomes.
3. Protein therapeutics can also be metabolized in the gastrointestinal tract and other tissues through ubiquitous proteolytic enzymes. The liver, kidneys and gastrointestinal tract are the primary sites of protein metabolism.
Chemical translocation & molecular fateSumer Pankaj
A toxicant is any toxic (harmful) substance which are often used to denote substances made by humans or introduced into the environment by human activity, in contrast to toxins, which are toxicants produced naturally by a living organism.
Toxicants are poisonous and they can enter into the plants by the stomatal openings and by root absorption.
In animals these toxic compounds may enter by ingestion, inhalation and dermal absorption.
Translocation may be defined as a process which converts thee lipophilic compounds to more hydrophilic metabolites so that it can pass through the cell membrane.
Biochemical alteration of chemicals such as nutrients, amino acids, toxins, and drugs in the body through certain processes like oxidation, hydrolysis, conjugation with the help of some specific enzymes. This process is also know as Bio-transformation.
It is also needed to render nonpolar compounds polar so that they are not reabsorbed in renal tubules and are excreted.
The body typically deals with a foreign compound (DRUGS) by making it more water-soluble, to increase the rate of its excretion through the urine.
If there is no detoxification of the substance then the toxin or drug enters into ADR (Adverse Drug Reaction) phase which may disturb the normal functioning of the body.
This Bio-transformation generally takes place in the body to convert lipophilic compound to more hydrophilic compounds, so that it can be easily excreted out of the body.
This document summarizes a seminar on computational methods for drug disposition. It discusses two approaches to modeling drug disposition: qualitative and quantitative. The quantitative approach uses pharmacophore modeling and docking to study drug interactions, while the qualitative approach uses QSAR and QSPR to correlate molecular descriptors with ADMET properties. The document also reviews the key processes of drug disposition: absorption, distribution, metabolism, and excretion. It provides examples of two research articles, one on the placental disposition of the immunosuppressant tacrolimus, and another on the pharmacokinetics of miltefosine in mice and hamsters infected with Leishmania.
1. Endocytosis and exocytosis are processes by which cells move materials into and out of the cell through the cell membrane. Endocytosis involves a part of the cell membrane enclosing extracellular fluids and molecules and breaking off into a vesicle inside the cell. Exocytosis involves secretory vesicles fusing with the plasma membrane and releasing their contents outside the cell.
2. There are several types of endocytosis, including phagocytosis which engulfs large particles, pinocytosis which absorbs fluids, and receptor-mediated endocytosis which selectively uptakes specific molecules bound to cell surface receptors.
3. Exocytosis releases contents from secretory vesicles to the extracellular space by vesicle fusion with the plasma membrane. It is important for
This document discusses algosomes, a novel vesicular drug delivery system. Algosomes are spherical vesicles composed of 1-O-alkylglycerols, cholesterol, and dicetyl phosphate that can encapsulate and deliver drugs. They are prepared using film hydration method. Algosomes have advantages like increased bioavailability and drug solubility. Characterization tests include determining vesicle size, zeta potential, drug content, and drug release kinetics using methods like microscopy, DSC, and Franz diffusion cells. Algosomes show potential for targeted delivery of anticancer drugs due to the bioactive properties of their components.
A cell consists of various molecules or substances.pdfstudywriters
A cell contains various molecules or metabolites that undergo metabolic reactions catalyzed by enzymes. Changes in enzyme activity can affect metabolic fluxes and metabolite concentrations in complex ways. Metabolomics studies how levels of metabolites are affected by changes in enzymes or other cellular processes. It faces challenges such as genetic variation between individuals, choice of instrumentation, and biomarker identification.
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In vitro screening for evaluation of drugs ADMET propertiesdilip kumar tampula
The document discusses pre-clinical in vitro screening techniques used to evaluate drugs' absorption, distribution, metabolism, excretion and toxicity (ADMET) properties early in the drug discovery process. It describes assays for various ADMET properties including partition coefficient, aqueous solubility, metabolic stability, plasma protein binding, and toxicity. The assays allow rapid evaluation of compounds with low amounts of material and help identify those with favorable pharmacokinetic and safety profiles to progress in development. The goal is to incorporate ADMET screening earlier to simultaneously optimize all drug properties.
This document provides an overview of biochemistry and pharmacology concepts. It discusses drug absorption, distribution, and excretion. It describes how drugs pass through cell membranes via filtration or active/passive transport. It also explains how drugs bind to plasma proteins and are metabolized in the liver and excreted by the kidneys or bile. The document then summarizes the mechanisms of action of antibiotics and antivirals, such as by inhibiting bacterial cell wall synthesis, protein synthesis, or viral DNA replication.
This document discusses various in vitro, in vivo, and in situ methods used to study drug absorption. It describes several in vitro techniques like partition coefficient studies, artificial membrane models, and cell culture models. It also explains various in vivo methods like direct blood/urine sampling and indirect pharmacological response studies in animals. Finally, it covers in situ techniques like intestinal perfusion that better simulate in vivo conditions compared to in vitro models. The document provides detailed descriptions of specific methods like the everted sac technique, diffusion cell method, and stomach perfusion studies in rats.
The plasma membrane surrounds cells and organelles, protecting the interior while regulating what passes in and out. It is a selectively permeable lipid bilayer containing proteins. The fluid mosaic model describes its structure as lipids and proteins moving freely within. Membranes are composed mainly of phospholipids, cholesterol, and glycolipids, with integral and peripheral proteins embedded. Transport across membranes includes passive diffusion, facilitated diffusion using carrier proteins, and active transport using ATP. Receptors on the surface receive signals from outside the cell.
Rational drug design begins by identifying a biological target implicated in disease. Drugs are then designed to modulate this target's activity in order to treat the disease. For a target to be suitable, there must be evidence it is disease-relevant and capable of binding small molecules. Once identified, the target is cloned, expressed, and purified. This allows high-throughput screening of chemical libraries to identify candidates that modify the target. Successful candidates should have properties predicting oral availability and low toxicity. Prodrugs and combinatorial chemistry are approaches that can improve drug properties and efficiency of discovery.
Toxicokinetics is the study of how the body processes toxic materials through absorption, distribution, metabolism and excretion (ADME). Absorption involves passage of toxicants across biological membranes, mainly through simple diffusion or specialized transport mechanisms. Distribution of toxicants through the body is determined by volume of distribution. Metabolism transforms toxicants into more water-soluble compounds through phase I (oxidation, reduction, hydrolysis) and phase II (conjugation) reactions. Excreted routes include renal excretion through urine and extra-renal excretion through bile, lungs, mammary glands and other secretions, terminating the toxicological effects.
This document discusses drug excretion and elimination from the body. It covers the major organs and processes involved, including the kidneys, lungs, bile/intestinal systems. Kidneys are the primary route of elimination for water-soluble drugs through glomerular filtration, tubular secretion, and reabsorption. Other topics covered include enterohepatic recirculation, factors influencing renal excretion, first vs zero order elimination kinetics, half-life, clearance, volume of distribution, and factors necessary for therapeutic drug monitoring.
The document discusses the disposition of chemicals in the body, including absorption, distribution, metabolism and excretion. It covers various factors that influence these processes such as lipid solubility, plasma protein binding, organ blood flow and enzyme activity. The kinetics of chemical elimination from the body is also described, particularly first-order elimination kinetics and the relationship between half-life, volume of distribution and clearance.
The document discusses the disposition of chemicals in the body, including absorption, distribution, metabolism and excretion. It covers various routes of exposure like oral, dermal and inhalation. Key concepts covered are factors affecting absorption, distribution between tissues and body compartments, biotransformation in the liver and excretion through kidneys, bile and other routes. The kinetics of chemical elimination from the body via first-order processes is also summarized.
This document discusses factors that affect oral drug absorption. It describes three main categories of factors: physiological, physical-chemical, and formulation factors. Under physiological factors, it discusses membrane physiology, how drugs pass membranes through different transport mechanisms like passive diffusion and active transport, and gastrointestinal physiology. It provides details on the anatomy and environments of different parts of the GI tract and how they impact drug absorption. It also discusses gastric emptying time and how it affects drug absorption.
This document provides an introduction to pharmacology and toxicology. It discusses the principles of how drugs interact with receptors in the body, including agonist and antagonist drug interactions. It also covers the pharmacokinetic principles of how drugs are absorbed, distributed, and eliminated from the body. This involves processes like permeation through aqueous and lipid barriers, as well as special carriers and pumps that facilitate drug transport. The goal is for drugs to safely reach their intended site of action and then be eliminated from the body.
Pharmacokinetics is the study of how the body affects drugs over time through absorption, distribution, metabolism, and excretion. Drugs move into, within, and out of the body through various transport mechanisms like passive diffusion, facilitated diffusion, and active transport. Factors like plasma protein binding, organ function, and route of administration influence a drug's absorption, distribution to tissues, metabolism by the liver, and excretion by the kidneys, lungs, bile, sweat, saliva or breast milk. Understanding these pharmacokinetic principles is important for predicting how drugs will behave in the body.
1. The major pathways for elimination of protein therapeutics are proteolysis and metabolism, with molecular weight being a major determinant of the specific elimination mechanisms.
2. Smaller proteins and peptides are filtered by the kidneys and undergo proteolysis, while larger proteins are taken up by the liver via receptor-mediated endocytosis and degraded in lysosomes.
3. Protein therapeutics can also be metabolized in the gastrointestinal tract and other tissues through ubiquitous proteolytic enzymes. The liver, kidneys and gastrointestinal tract are the primary sites of protein metabolism.
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A toxicant is any toxic (harmful) substance which are often used to denote substances made by humans or introduced into the environment by human activity, in contrast to toxins, which are toxicants produced naturally by a living organism.
Toxicants are poisonous and they can enter into the plants by the stomatal openings and by root absorption.
In animals these toxic compounds may enter by ingestion, inhalation and dermal absorption.
Translocation may be defined as a process which converts thee lipophilic compounds to more hydrophilic metabolites so that it can pass through the cell membrane.
Biochemical alteration of chemicals such as nutrients, amino acids, toxins, and drugs in the body through certain processes like oxidation, hydrolysis, conjugation with the help of some specific enzymes. This process is also know as Bio-transformation.
It is also needed to render nonpolar compounds polar so that they are not reabsorbed in renal tubules and are excreted.
The body typically deals with a foreign compound (DRUGS) by making it more water-soluble, to increase the rate of its excretion through the urine.
If there is no detoxification of the substance then the toxin or drug enters into ADR (Adverse Drug Reaction) phase which may disturb the normal functioning of the body.
This Bio-transformation generally takes place in the body to convert lipophilic compound to more hydrophilic compounds, so that it can be easily excreted out of the body.
This document summarizes a seminar on computational methods for drug disposition. It discusses two approaches to modeling drug disposition: qualitative and quantitative. The quantitative approach uses pharmacophore modeling and docking to study drug interactions, while the qualitative approach uses QSAR and QSPR to correlate molecular descriptors with ADMET properties. The document also reviews the key processes of drug disposition: absorption, distribution, metabolism, and excretion. It provides examples of two research articles, one on the placental disposition of the immunosuppressant tacrolimus, and another on the pharmacokinetics of miltefosine in mice and hamsters infected with Leishmania.
1. Endocytosis and exocytosis are processes by which cells move materials into and out of the cell through the cell membrane. Endocytosis involves a part of the cell membrane enclosing extracellular fluids and molecules and breaking off into a vesicle inside the cell. Exocytosis involves secretory vesicles fusing with the plasma membrane and releasing their contents outside the cell.
2. There are several types of endocytosis, including phagocytosis which engulfs large particles, pinocytosis which absorbs fluids, and receptor-mediated endocytosis which selectively uptakes specific molecules bound to cell surface receptors.
3. Exocytosis releases contents from secretory vesicles to the extracellular space by vesicle fusion with the plasma membrane. It is important for
This document discusses algosomes, a novel vesicular drug delivery system. Algosomes are spherical vesicles composed of 1-O-alkylglycerols, cholesterol, and dicetyl phosphate that can encapsulate and deliver drugs. They are prepared using film hydration method. Algosomes have advantages like increased bioavailability and drug solubility. Characterization tests include determining vesicle size, zeta potential, drug content, and drug release kinetics using methods like microscopy, DSC, and Franz diffusion cells. Algosomes show potential for targeted delivery of anticancer drugs due to the bioactive properties of their components.
A cell consists of various molecules or substances.pdfstudywriters
A cell contains various molecules or metabolites that undergo metabolic reactions catalyzed by enzymes. Changes in enzyme activity can affect metabolic fluxes and metabolite concentrations in complex ways. Metabolomics studies how levels of metabolites are affected by changes in enzymes or other cellular processes. It faces challenges such as genetic variation between individuals, choice of instrumentation, and biomarker identification.
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ADME – A Key To An Effective And Safe Drug – Selvita.pdf
1. Often in the press or online portals, you can find news
that someone (usually a lone scientist) has discovered
a cure for some extremely important disease. Such
news stories appear and will continue to appear, and
yet the new drugs they were talking about were as
non-existent as they were. How does this happen?
What is it that makes molecules, often so promising in
laboratory studies, not end up as new drugs? The
answer is ADME. But what is ADME?
ADME – A Key To An Effective And
Safe Drug – Selvita
2. What does ADME stand for?
ADME is an acronym used in pharmacology. It stands
for Absorption, Distribution, Metabolism, and
Excretion. In short, these are the processes that take
place in our body in the context of foreign substances,
including drugs. It is how drugs are absorbed,
transported around our body, metabolized, and
excreted that affects whether a drug is effective
(reaches its destination) and safe (does not cause side
effects).
Why is ADME important?
Imagine that you design a new therapeutic molecule.
You test its activity in vitro and get amazing, even
spectacular, results. So there is nothing left to do but
test the molecule on animals. And there is a surprise. It
turns out that in an animal model, the results are not
very satisfactory. Why? Well. You have to ensure that
the molecule still reaches its target and that it has a
therapeutic effect. To do this, the properties of ADME
should be studied in parallel with activity, and the
results incorporated into the models used to design
molecules.
3. Kinetic solubility
Thermodynamic solubility
LogP/ LogD
Caco-2 permeability assay
PAMPA
MDCK permeability assay
What are ADME studies?
ADME can be studied at the in vitro and in vivo levels
(determining the pharmacokinetic profile). During the
discovery and even early development phases, in vitro
testing plays a huge role. With appropriately designed
analytical methods, it is possible to study intestinal
drug absorption, hepatic metabolism, mode of
elimination, and the form in which the molecule is
eliminated. Among the most popular tests included in
ADME are: LogD/LogP, Caco-2 absorption test, MDCK
absorption test, PAMPA, metabolic stability, and
metabolite identification.
Sometimes a T for toxicity is added to the ADME
package. This results in an expanded suite of tests
called ADMET or ADMETox.
So let’s divide ADME tests according to the property
being tested.
Absorption
4. The first three of these tests, at first glance, have
nothing to do with absorption. Nothing could be
further from the truth. Let’s start with solubility. Only
a dissolved compound is able to cross the intestinal-
blood barrier. So it directly affects the possibility of
absorption and correlates closely with bioavailability. I
mentioned two solubility tests: thermodynamic
solubility and kinetic solubility. How do they differ
from each other? Let’s start with thermodynamic
solubility. The result of this test tells about the
solubility of a substance in thermodynamic
equilibrium. The undissolved substance is added to a
buffer of a certain pH until supersaturated, and then
stirred for 24 hours for the system to reach
thermodynamic equilibrium. The concentration of the
solute in solution is then tested. Thermodynamic
solubility is usually determined at three pH levels
corresponding to the pH of the digestive system and
plasma. It is this property that is crucial for the
absorption of the substance.
The situation is slightly different with kinetic solubility.
This test is performed to determine the solubility of a
substance under conditions used in various in vitro
tests. Usually, the starting point is a stock solution of
the substance (for example, in DMSO). Solubility is
tested by diluting the stock solution with the buffer
under test to a specified concentration, e.g. 500 μM.
After stirring for a specified time, e.g., 1 hour, the
content of the substance in the tested solution is
determined.
5. Performing this test allows research teams to ensure
that the test substance is present in the dissolved
form under the conditions in which laboratory tests
are performed.
The third non-obvious parameter determined by
ADME is the partition coefficient between the water
fraction and octanol, or so-called LogP. Octanol does
not naturally occur in the body; however, this value
closely correlates with the molecule’s ability to be
absorbed into the body through passive absorption
and also with the volume of distribution. The volume
of distribution, in turn, tells whether the compound
penetrates from the plasma into the tissues and is able
to reach its therapeutic target.
Traditionally, the partition coefficient was determined
by preparing a water/octanol system, adding the test
compound to it, shaking the system vigorously, and
then assessing the concentration of the compound in
the individual fractions. Nowadays, it can also be
determined using special columns for HPLC.
The PAMPA (Parallel Artificial Membrane Permeability
Assay) test is often performed. This is a test that
investigates passive transport across lipid membranes.
For this test, special multi-well plates are used, with a
bottom made of a special membrane. A lipid solution,
e.g., soya lecithin, is applied to this membrane, which
thus mimics a lipidic biological membrane.
6. Solutions of the test substances are then added to the
wells, and the plate is placed in a second (collection)
plate, which contains buffer without the addition of
the test substance. After a defined incubation time,
the concentration in both plates is assessed, and the
transport rate is determined.
The most developed laboratory tests in which uptake
is investigated are cell assays using the Caco-2 and
MDCK lines.
The Caco-2 line is a polyclonal cell line isolated from
human colon cancer. Cultured under appropriate
conditions, they adopt the morphology and
functionality of small intestinal epithelial cells. They
can therefore be used to test the transport of particles
from the intestine into the blood. The superiority of
this assay over the previously mentioned ones is that
the cells are equipped with transporters and enzymes
and therefore have complete gut-blood barrier
functionality. Thus, it is possible to determine the rate
of absorption, which consists of passive transport,
active transport, return transport, and also
metabolism (first-pass effect).
While the PAMPA test uses quite high concentrations
of substances and thus simple UV-VIS spectroscopy
can be used to determine concentrations, this is not
possible with the Caco-2 test. High substance
concentrations could be toxic to the cells and could
interfere with the test result.
7. Metabolic stability
Identification of metabolites
The most commonly used concentration is 10 μM. In
addition, the matrix is more complex. Cell metabolites,
proteins, and sometimes the addition of BSA are used
for the test. Therefore, the concentration in the
samples is determined by LC-MS/MS analysis, usually
using triple quadrupole or q-trap instruments.
In order to be completely functional, Caco-2 cells need
to be cultured for 21 days in special multi-well plates
with a semi-permeable membrane. During this time,
the cells form a monolayer and differentiate to obtain
the morphology and functionality of the small
intestinal cells. The platelets are placed in the
collection plates. Transport is studied in both
directions, i.e., intestine blood (adding the compound
solution to the top of the cells) and blood-gut (adding
the compound solution to the stripping plate). In this
way, it is possible to determine the so-called Efflux
ratio, which tells what is the rate of efflux transport,
carried out by special membrane proteins
Metabolism
When talking about drugs, we must bear in mind that
for our organisms they are foreign substances, the so-
called Xenobiotics. Organisms have developed a
number of mechanisms to protect them from
xenobiotics, as toxic substances can be found among
them.
8. Among these mechanisms, metabolism and excretion
can be enumerated. While excretion seems obvious
(the sooner we get rid of a harmful substance, the
better), metabolism is no longer so. However, our
organisms have an interesting ability to modify foreign
substances so that they are less toxic or more easily
excreted. It does this through their metabolism, i.e.,
chemical modification catalyzed by enzymes. Drug
metabolism occurs throughout the body, but the main
organ that does this is the liver.
Metabolism of xenobiotics is divided into two phases.
Phase I – functionalization occurs in the smooth
endoplasmic reticulum. It is catalyzed by a family of
enzymes collectively known as cytochrome P450,
which change certain functional groups of chemical
molecules in a red-ox process. They carry out
reactions such as deamidation, deamination,
hydroxylation, dehydroxylation, etc. As a result, the
resulting molecules are usually less toxic. Sometimes,
however, so-called reactive metabolites can be
formed, which can cause further damage to the body
by causing, for example, oxidation of proteins or
nucleic acids.
Phase II – conjugation. Occurs in the cytoplasm of
cells. It involves the attachment of highly hydrophilic
functional groups to molecules such as the glucuronic
acid residue. This is to facilitate the filtering of these
molecules in the kidney and their removal with the
urine.
9. Metabolism can be studied at two levels: biochemical
and cellular. At the cellular level, this can be done
using isolated hepatocytes. However, this is rarely
used due to the high cost of obtaining hepatocytes
and also the rather high requirements of these cells.
The most commonly used are the subcellular fraction
of microsomes (containing the endoplasmic reticulum)
and the S9 fraction (containing microsomes and
cytoplasm). The test compound is incubated with the
subcellular fraction with the addition of appropriate
cofactors, and the loss of substance over time is
examined by LC-MS/MS. By using this technique, it is
also possible to identify metabolites.
The study of metabolism is extremely important at an
early stage of research. The enzymes responsible for
metabolism are characterized by high inter-species
variability. It is possible that a molecule is metabolized
extremely rapidly in rodents, e.g. by fractions derived
from the liver of mice or rats, while being completely
absent from metabolic pathways in humans. This can
greatly complicate issues of selecting an appropriate
animal model for in vivo studies or subsequent
attempts to extrapolate results to the human body.
On the occasion of metabolism, it is worth mentioning
the study of cytochrome P450 inhibition. This family
of proteins metabolizes many drugs. The 3A4 isoform
of this enzyme alone catalyzes the metabolism of more
than 80% of all small-molecule drugs.
10. Not surprisingly, there can be interactions between
different drugs due to their mutual metabolism. If a
molecule is metabolized, it simultaneously becomes
an inhibitor of the enzyme that is responsible for its
metabolism. When other drugs are taken, this can lead
to an increase in their concentration and subsequent
side effects. For some drugs, this is extremely
important, e.g., in the case of neurological drugs,
which often have a narrow safety window, and the
blood-brain barrier makes it difficult to remove them
from the brain.
Metabolism does not only occur in the liver. Various
enzymes that can induce it are found, among others, in
the plasma. These include, for example, esterases
responsible for breaking down esters. Therefore,
stability tests are often performed in plasma. For this
purpose, the test substance is added to the plasma,
and its plasma content is determined at successive
time points. This is an important test also for the
reliability of another test that is performed as part of
ADME – binding to plasma proteins. For some
molecules, stability testing in plasma is extremely
important are so-called ‘prodrugs’, i.e. molecules that
do not have therapeutic activity on their own, but
acquire it after metabolization. Often, scientists who
design drugs construct them in the form of esters so
that they are more easily absorbed. Then, through the
action of esterases present in the plasma, the pro-drug
molecule is metabolized to its active form.
11. Distribution
The absorption of a drug into the body does not yet
mean that it will reach its target. Neurological drugs
need to reach the brain to bind to their receptors
there. Others have to go inside cells to be affected by
their metabolism or to combine with intracellular
receptors. And even if they reach the target organs, it
must be remembered that only unbound molecules
show a therapeutic effect. Many drugs, however, use
porters when traveling through our bodies and bind to
plasma proteins.
For this reason, an extremely important test that is
performed as part of ADME is the study of binding to
plasma proteins. Normally, the analyzed compound is
added to the plasma, and dialysis is performed. Only
the unbound fraction of the compound is able to pass
into the dialysate. After a defined dialysis time, a
determination of the concentration of the substance
in both fractions is performed (in the fraction with
plasma after prior denaturation of the proteins to
release the test substance).
12. In vitro ADME studies are able to answer many
questions. A very powerful tool is physiology-based
pharmacokinetics modeling, known as PBPK
(physiology-based pharmacokinetics modeling), which
uses results from in vitro and in vivo studies to predict
drug development behavior in the body. However, not
everything can be verified only at the in vitro level.
Sometimes the properties of a molecule make it
difficult to perform these tests. This can happen when
the molecule is highly hydrophobic or unstable in
plasma. Through in vivo studies, calculations in PBPK
models can also be validated and improved. We will
discuss how in vivo pharmacokinetics studies are
performed, the types of these studies, and the
information that can be obtained in the next article on
ADME.
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