Tew's work on redox and pharmacogenetics focused on the discovery and development of drugs. Alongside colleagues, he introduced a novel zebrafish model with a glutathione S-transferase π1 (gstp1) knockout, revealing insights into redox homeostasis, reductive stress, and responses to drugs inducing endoplasmic reticulum stress and the unfolded protein response. [ 15 ] [ 16 ]  His research has looked into the role of GTSP in cellular redox homeostasis and its over-expression in cancer drug resistance, particularly in the context of preclinical and clinical testing of the GSTP inhibitor TLK199 (Telintra) for treating myelodysplastic syndrome. [ 17 ]  He further revealed that the absence of microsomal glutathione transferase 1 (MGST1) impacts melanin biosynthesis and melanoma growth in mice and that, in numerous species, members of the GST family are involved in early hematopoiesis, [ 18 ]  and that the lack of GSTP in dendritic cells leads to increased proliferation, ROS levels and ERα levels, suggesting a role for GSTP in controlling ERα activity and dendritic cell function. [ 19 ]


Additionally, Tew and colleagues investigated how S-glutathionylation of the protein BiP, mediated by GSTP, contributes to acquired resistance to the multiple myeloma treatment bortezomib (Btz) by impacting BiP's foldase and ATPase activities. [ 20 ]  In another collaborative study published in  Scientific Reports , he found that S-glutathionylated serpins, specifically A1 and A3, are elevated in the blood of prostate cancer patients after radiation therapy, suggesting their potential as biomarkers for radiation exposure. [ 21 ]  He also explored melanoma cell lines resistant to reductive stress agents, showcasing changes in cell and mitochondrial morphology, metabolic preferences, and adaptive mechanisms in lethal reductive stress conditions. [ 22 ]


Tew has studied cancer strategies to devise new treatments. In a joint research, he highlighted the significance of microsomal glutathione transferase 1 (MGST1) in melanin biosynthetic pathways, revealing its role as a determinant of tumor progression, with MGST1 knockdown leading to depigmentation, increased oxidative stress, and hindered tumor growth. [ 23 ]  He also determined that inhibiting microsomal glutathione S-transferase 1 (MGST1) in melanoma enhances oxidative stress, increases sensitivity to anticancer drugs, and reduces metastasis, improving the effectiveness of therapies. [ 24 ]


Tew examined ME-344, a second-generation isoflavone with anticancer properties in 2019, demonstrating its impact on redox homeostasis, mitochondrial function, and specific targeting of heme oxygenase 1 (HO-1) in lung cancer cells. [ 25 ]  In 2020, he determined that ME-344 targets VDAC1 and VDAC2 in lung cancer cells, leading to ROS generation, Bax translocation, cytochrome c release, and apoptosis, highlighting their potential as therapeutic targets. [ 26 ]  He also assessed how reactive oxygen species (ROS) play a dual role in cancer evolution, influencing both tumorigenesis and cell death, and highlighted tumor cell adaptations in metabolism and antioxidant defenses to manage ROS levels during different stages of cancer development. [ 27 ]


Ferdinand Bernhard Vietz  (18 November 1772 in  Vienna  – 15 December 1815 in Vienna), was an Austrian pharmacologist, a Doctor of the Healing Arts and Professor of Forensic Medicine at the  University of Vienna , and is best known for  Icones Plantarum Medico-Oeconomico-Technologicarum cum Earum Fructus ususque Descriptione  (1800–1822), an 11-volume compilation of medicinal, culinary and decorative plant species consulted by pharmacologists during the early 1800s.  The noted cartographic engraver,  Ignaz Alberti , worked on the 1100 hand-coloured copperplate engravings on laid-watermarked paper and completed the work after the early death of Vietz. [ 1 ]


Volumes 1 and 2 were printed in  Latin  and  German  in adjacent columns. Volumes 3-10 have the title in German only. Volume 11 is a supplementary volume by Joseph Lorenz Kendl. In the introduction to Volume 1, Vietz lists a lengthy bibliography of consulted works, an enormous number of sponsors and a dedication to Maria Theresa,  Empress of Austria .


Vietz's monumental work is extremely rare, and the  British Natural History Museum  writes:
The work is “not being held in any other of the United Kingdom's national or public library collections. Only three copies have been found in North American libraries, of which two are certainly fragile and in need of conservation. One copy is in the Austrian National Library.”  [ 2 ]


On his death, Vietz was succeeded by  Joseph Bernt  (1770–1842), as professor of state medicine.


John Mitchell Watt  (1 December 1892 – 23 April 1980) was a 20th-century South African physician and pharmacologist.


He served in both World Wars. He made extensive catalogues of traditional African medicines. [ 1 ]


He was born in  Port Elizabeth  in  Cape Colony  on 1 December 1892. He was educated at the Grey Institute High School in Port Elizabeth. His family moved to  Scotland  and he completed his education at  Stirling High School .


He studied medicine at the  University of Edinburgh  graduating with an  MB ChB  in 1916. He then joined the  Royal Army Medical Corps .


In 1921 he became Professor of  Pharmacology  at  University College, Johannesburg .


In 1933 he was elected a Fellow of the  Royal Society of Edinburgh . His proposers were  John Phillips ,  Robert Burns Young ,  James Harvey Pirie  and Sir  William Wright Smith . [ 2 ]


In the  Second World War  he was in charge of medical supplies for the South African Defence Headquarters for the entire war.


In 1957 he joined the South African Institute for Medical Research. In 1965 he moved back to Britain to teach at the  Plymouth  College of Technology.


He went into semi-retirement in 1965, also moving to  Australia . He was a part-time Demonstrator in  Physiology  at the  University of Queensland .  Rand Afrikaans University  awarded him an honorary doctorate (LLD) for his academic writing in 1972.


He died in  Brisbane  on 23 April 1980.


He was married twice: firstly in 1920 to Yelena Nikonova, secondly in 1942 to Betty Gwendoline Lory.


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 describing how the body affects a specific substance after administration. [ 1 ]  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 based on mathematical modeling that places great emphasis on the relationship between drug plasma concentration and the time elapsed since the drug's administration. Pharmacokinetics is the study of how an organism affects the 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 .


Pharmacokinetics :


A number of phases occur once the drug enters into contact with the organism, these are described using the acronym ADME (or LADME if liberation is included as a separate step from absorption):


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 . The two phases of metabolism and excretion can be grouped together under the title  elimination .


The study of these distinct phases involves the use and manipulation of basic concepts in order to understand the process dynamics. For this reason, in order to 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.


The following are the most commonly measured pharmacokinetic metrics: [ 5 ]  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/L'. Similarly, other units in the table may be expressed in units of an equivalent  dimension  by scaling. [ 6 ]


where

 C

 av

 ,

 ss

 =

 A
 U

 C

 τ
 ,

 ss

 τ

 {\displaystyle C_{{\text{av}},{\text{ss}}}={\frac {AUC_{\tau ,{\text{ss}}}}{\tau }}}


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 once regular dosing of a drug is started, steady state is reached after 3 to 5 times its half-life. In steady state and in linear pharmacokinetics, AUC τ =AUC ∞ . [ 8 ]


Models have been developed to simplify conceptualization of the many processes that take place in the interaction between an organism and a chemical substance. Pharmacokinetic modelling may be performed either by noncompartmental or  compartmental  methods.  Multi-compartment models  provide the best 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 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 .


Models generally take the form of  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. A variety of analysis techniques may be used to develop models, such as  nonlinear regression  or curve stripping.


Noncompartmental methods estimate PK parameters directly from a table of concentration-time measurements. Noncompartmental methods are versatile in that they do not assume any specific model and generally produce accurate results acceptable for bioequivalence studies. 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 to maximum concentration), CL and Vd can also be reported using NCA methods.


Compartment models methods estimate the concentration-time graph by modeling it as a system of differential equations. These models are based on a consideration of an organism as a number of related  compartments . Both single compartment and  multi-compartment models  are in use. 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 noncompartmental analysis is the ability to modify parameters and to extrapolate to novel situations. The disadvantage is the difficulty in developing and validating the proper model. Although compartment models have the potential to realistically model the situation within an organism, models inevitably make simplifying assumptions and will not be applicable in all situations. However complicated and precise a 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.


The simplest PK compartmental model is the one-compartmental PK model. This models an organism as one homogenous compartment. This  monocompartmental model  presupposes that  blood plasma  concentrations of the drug are the only information needed to determine the drug's concentration in other fluids and tissues. For example, the concentration in other areas may be approximately related by known, constant factors to the blood plasma concentration.


In this one-compartment model, the most common model of elimination is  first order kinetics , where the elimination of the drug is directly proportional to the drug's concentration in the organism. This is often called   linear pharmacokinetics , as the change in concentration over time can be expressed as a linear differential equation

 d
 C

 d
 t

 =
 −

 k

 el

 C

 {\textstyle {\frac {dC}{dt}}=-k_{\text{el}}C}

 . Assuming a single IV bolus  dose  resulting in a concentration

 C

 initial

 {\displaystyle C_{\text{initial}}}

  at time

 t
 =
 0

 {\displaystyle t=0}

 , the equation can be solved to give

 C
 =

 C

 initial

 ×

 e

 −

 k

 el

 ×
 t

 {\displaystyle C=C_{\text{initial}}\times e^{-k_{\text{el}}\times t}}

 .


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.


Two-compartment models 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. [ 9 ]


In the real world, each tissue will have its own distribution characteristics and none of them will be strictly linear. The two-compartment 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. 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:


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. [ 9 ]  The most complex PK models (called  PBPK  models) rely on the use of physiological information to ease development and validation.


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:


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


At a practical level, a drug's bioavailability can be defined as the proportion of the drug that reaches the systemic circulation. 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).


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:


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:


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: [ 12 ]


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


where  Q  is the drug's purity. [ 12 ]


where

 V
 a

 {\displaystyle Va}

  is the drug's rate of administration and

 τ

 {\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

 p
 K
 a

 {\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:


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.


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. [ 13 ] [ 14 ]


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. [ 15 ] [ 16 ] [ 17 ]


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 . [ 18 ]  Recent studies show that  Secondary electrospray ionization  (SESI-MS) can be used in drug monitoring, presenting the advantage of avoiding animal sacrifice. [ 19 ]


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. [ 20 ] [ 21 ] [ 22 ]  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 with  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).


medication


(HIV) medication


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. [ 23 ]  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: [ 24 ]


Ecotoxicology  is the branch of science that deals with the nature, effects, and interactions of substances that are harmful to the environment such as  microplastics  and other  biosphere  harmful substances. [ 25 ] [ 26 ]  Ecotoxicology is studied in pharmacokinetics due to the substances responsible for harming the environment such as  pesticides  can get into the bodies of living organisms. The health effects of these chemicals is thus subject to research and  safety trials  by government or international agencies such as the  EPA  or  WHO . [ 27 ] [ 28 ]   How long these chemicals stay in the body , the  lethal dose  and other factors are the main focus of Ecotoxicology.


All model based software above.


Global centres with the highest profiles for providing in-depth training include the Universities of  Buffalo ,
 Florida ,  Gothenburg ,  Leiden ,  Otago ,  San Francisco ,  Beijing , Tokyo,  Uppsala ,  Washington ,  Manchester , Monash University, and University of  Sheffield . [ 1 ]


Absorption  is the journey of a drug travelling from the site of administration to the site of action. [ 1 ] [ 2 ]


The drug travels by some  route of administration  ( oral ,  topical-dermal , etc.) in a chosen  dosage form  (e.g.,  tablets ,  capsules , or in  solution ). [ 3 ]  Absorption by some other routes, such as  intravenous therapy ,  intramuscular injection ,  enteral nutrition , is even more straightforward and there is less variability in absorption and  bioavailability  is often near 100%.  Intravascular  administration does not involve absorption, and there is no loss of drug. [ 4 ]  The fastest route of absorption is  inhalation . [ 5 ]


Absorption is a primary focus in  drug development  and  medicinal chemistry , since a drug must be absorbed before any medicinal effects can take place.  Moreover, the drug's pharmacokinetic profile can be easily and significantly changed by adjusting factors that affect absorption.


Oral ingestion is the most common route of administration of pharmaceuticals. [ 6 ]  Passing through the  esophagus  to the  stomach , the contents of the capsule or tablet are absorbed by the  GI tract . The absorbed pharmaceutical is then passed through the  liver  and  kidneys . [ 7 ]


The rate of dissolution is a key target for controlling the duration of a drug's effect, and as such, several dosage forms that contain the same active ingredient may be available, differing only in the rate of dissolution. If a drug is supplied in a form that is not readily dissolved, it may be released gradually and act for longer. Having a longer duration of action may improve  compliance  since the medication will not have to be taken as often.  Additionally, slow-release dosage forms may maintain concentrations within an acceptable therapeutic range over a longer period, whereas quick-release dosage forms may have sharper peaks and troughs in serum concentration. [ 8 ]


The rate of dissolution is described by the  Noyes–Whitney equation  as shown below:


As can be inferred from the Noyes–Whitney equation, the rate of dissolution may be modified primarily by altering the surface area of the solid by altering the particle size (e.g., with  micronization ). For many drugs, reducing the particle size reduces the dose needed to achieve the same therapeutic effect. The particle size reduction increases the  specific surface area  and the dissolution rate and does not affect solubility.


The rate of dissolution may also be altered by choosing a suitable  polymorph  of a compound. Different polymorphs have different solubility and dissolution rate characteristics.  Specifically, crystalline forms dissolve slower than amorphous forms since they require more energy to leave the lattice during dissolution. The stablest crystalline polymorph has the lowest dissolution rate. Dissolution also differs between anhydrous and hydrous forms of a drug. Anhydrous forms often dissolve faster but sometimes are less soluble.


Esterification  is also used to control solubility. For example,  stearate  and estolate  esters  of drugs have decreased solubility in  gastric fluid . Later,  esterases  in the  gastrointestinal tract  (GIT) wall and blood  hydrolyze  these esters to release the parent drug.


Coatings on a tablet or pellet may act as barriers to reducing the dissolution rate. Coatings may also be used to control where dissolution takes place. For example,  enteric coatings  only dissolve in the  basic  environment of the  intestines .


Drugs held in solution do not need to be dissolved before being absorbed.


Lipid-soluble drugs are absorbed more rapidly than water-soluble drugs. [ 9 ]


The  gastrointestinal tract  is lined with  epithelial cells .  Drugs must pass through or permeate these cells to be absorbed into the  bloodstream .   Cell membranes  may act as barriers to some drugs.  They are essentially  lipid bilayers  which form  semipermeable membranes .  Pure lipid bilayers are generally permeable only to small, uncharged solutes.  Hence, whether or not a molecule is  ionized  will affect its absorption, since ionic molecules are charged.  Solubility favors charged species, and permeability favors neutral species.  Some molecules have special exchange proteins and channels to facilitate movement from the lumen into the circulation. [ vague ]


Ions cannot passively diffuse through the gastrointestinal tract because the epithelial cell membrane is made up of a  phospholipid bilayer , comprising two layers of phospholipids in which the charged hydrophilic heads face outwards and the uncharged hydrophobic fatty acid chains are in the middle of the layer. The fatty acid chains repel ionized, charged molecules. This means that the ionized molecules cannot pass through the intestinal membrane and be absorbed.


The  Henderson-Hasselbalch equation  offers a way to determine the proportion of a substance that is ionized at a given pH.  In the stomach, drugs that are  weak acids  (such as  aspirin ) will be present mainly in their non-ionic form, and  weak bases  will be in their ionic form.  Since non-ionic species diffuse more readily through  cell membranes , weak acids will have a higher absorption in the highly acidic  stomach .


However, the reverse is true in the  basic  environment of the intestines—weak bases (such as  caffeine ) will diffuse more readily since they will be non-ionic.


This aspect of absorption has been targeted by medicinal chemists.  For example, they may choose an  analog  that is more likely to be in a non-ionic form.  Also, the chemists may develop  prodrugs  of a compound—these chemical variants may be more readily absorbed and then metabolized by the body into the active compound.  However, changing the structure of a molecule is less predictable than altering dissolution properties, since changes in chemical structure may affect the  pharmacodynamic  properties of a drug.


The solubility and permeability of a drug candidate are important physicochemical properties the scientist wants to know as early as possible. [ 10 ]


Absorption also varies depending on bioactivity, resonance, the inductive effect, isosterism, bio-isosterism, and consideration, amongst others.


Types of absorption in pharmacokinetics include the following: [ 11 ]


An  active metabolite , or  pharmacologically active metabolite  is  a biologically active  metabolite  of a  xenobiotic  substance, such as a drug or environmental chemical. Active metabolites may produce therapeutic effects, as well as harmful effects. [ 1 ]


An active metabolite results when a drug is metabolized by the body into a modified form which produces effects in the body. Usually these effects are similar to those of the  parent drug  but weaker, [ citation needed ]  although they can still be significant (see e.g.  11-hydroxy-THC ,  morphine-6-glucuronide ). Certain drugs such as  codeine  and  tramadol  have metabolites ( morphine  and  O -desmethyltramadol  respectively) that are stronger than the parent drug [ 2 ] [ 3 ] [ 4 ]  and in these cases the metabolite may be responsible for much of the therapeutic action of the parent drug. Sometimes, however, metabolites may produce toxic effects and patients must be monitored carefully to ensure they do not build up in the body. This is an issue with some well-known drugs, such as  pethidine  (meperidine) and  dextropropoxyphene . [ 4 ] [ 5 ]


Sometimes drugs are formulated in an inactive form that is designed to break down inside the body to form the active drug. These are called  prodrugs . The reasons for this type of formulation may be because the drug is more stable during manufacture and storage as the prodrug form, or because the prodrug is better absorbed by the body or has superior  pharmacokinetics  (e.g.,  lisdexamphetamine ). [ 6 ]


ADME  is the four-letter abbreviation (acronym) for  absorption ,  distribution ,  metabolism , and  excretion , and is mainly used in fields such as  pharmacokinetics  and  pharmacology . The four letter stands for descriptors quantifying how a given drug interacts within body over time. The term ADME was first introduced in the 1960s, and has become a standard term widely used in scientific literature, teaching, drug regulations, and clinical practice. [ 1 ]


ADME, 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 . Sometimes,  liberation  and/or  toxicity  are also considered, yielding LADME, ADMET, or LADMET.


For a compound to reach a tissue, it usually must be taken into the  bloodstream  – often via  mucous  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 ).  Routes of administration  are an important consideration.


The compound needs to be carried to its effector site, most often via the bloodstream. From there, the compound may distribute into muscle 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 .


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  redox  enzymes, termed  cytochrome P450  enzymes.  As metabolism occurs, the initial (parent) compound is converted to new compounds called  metabolites .  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 (see  prodrug ).


Compounds and their  metabolites  need to be removed from the body via  excretion , usually through the  kidneys  (urine) or in the feces. Unless excretion is complete, accumulation of foreign substances can adversely affect normal metabolism.


There are three main 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 main method of excretion is through the lungs (e.g. anesthetic gases).


Excretion of drugs by the kidney involves 3 main mechanisms:


Sometimes, the potential or real  toxicity  of the compound is taken into account ( ADME-Tox  or  ADMET ).  Parameters used to characterize toxicity include the median lethal dose ( LD 50 ) and  therapeutic index .


Computational chemists  try to predict the ADME-Tox qualities of compounds through methods like  QSPR  or  QSAR .


The  route of administration  critically influences ADME.


In the field of  pharmacokinetics , the  area under the curve  ( AUC ) is the  definite integral  of the  concentration  of a  drug  in  blood plasma  as a function of time (this can be done using  liquid chromatography–mass spectrometry [ 1 ] ). In practice, the drug concentration is measured at certain discrete points in time and the  trapezoidal rule  is used to estimate AUC. In pharmacology, the area under the plot of plasma concentration of a drug  versus  time after dosage (called “area under the curve” or AUC) gives insight into the extent of exposure to a drug and its  clearance rate  from the body. [ 2 ]


The AUC (from zero to infinity) represents the  total drug exposure across time . AUC is a useful metric when trying to determine whether two  formulations  of the same dose (for example a  capsule  and a  tablet ) result in equal amounts of  tissue  or plasma exposure. Another use is in the  therapeutic drug monitoring  of drugs with a narrow  therapeutic index . For example,  gentamicin  is an  antibiotic  that can be  nephrotoxic  ( kidney  damaging) and  ototoxic  (hearing damaging); measurement of  gentamicin  through concentrations in a patient's plasma and calculation of the AUC is used to guide the dosage of this drug. [ 3 ]


AUC becomes useful for knowing the average concentration over a time interval, AUC/t. Also, AUC is referenced when talking about  elimination . The amount eliminated by the body (mass) = clearance (volume/time) * AUC (mass*time/volume). [ citation needed ] [ 4 ]


In  pharmacokinetics ,  bioavailability  generally refers to the fraction of a drug that is absorbed systemically and is thus available to produce a  biological  effect. This is often measured by quantifying the "AUC". In order to determine the respective AUCs, the  serum  concentration vs. time plots are typically gathered using C-14 labelled drugs and AMS ( accelerated mass spectrometry ). [ 5 ]


Bioavailability  can be measured in terms of "absolute bioavailability" or "relative bioavailability".


Absolute bioavailability  refers to the  bioavailability  of a drug when administered via an  extravascular  dosage form (i.e. oral tablet,  suppository ,  subcutaneous , etc.) compared with the bioavailability of the same drug administered  intravenously  (IV). This is done by comparing the AUC of the non-intravenous dosage form with the AUC for the drug administered intravenously. This fraction is normalized by multiplying by each dosage form's respective dose. [ 6 ]


Relative bioavailability  compares the bioavailability between two different dosage forms. Again, the relative AUCs are used to make this comparison and relative doses are used to normalize the calculation.


AUC of  glucose  concentration change following food intake is used to calculate the  glycemic index . [ 7 ]


The use of  trapezoidal rule  in AUC calculation was known in literature by no later than 1975, in J.G. Wagner's  Fundamentals of Clinical Pharmacokinetics . A 1977 article compares the "classical" trapezoidal method to a number of methods that take into account the typical shape of the concentration plot, caused by  first-order kinetics . [ 8 ]


Notwithstanding the above knowledge, a 1994  Diabetes Care  article by Mary M. Tai purports to have independently discovered the trapezoidal rule. [ 9 ]  In Tai's response to the later  letters to the editors , she explained that the rule was new to her colleagues, who relied on grid-counting. [ 10 ]  Tai's paper has been discussed as a case of  scholarly peer review  failure. [ 11 ]


Despite the number of mathematically superior  numerical integration  schemes (such as those outlined in  Wagner & Ayres 1977 ), the trapezoidal rule remains the convention for AUC calculation. Later focus on improving the accuracy of AUC calculation shifted from improving the method to improving the sampling scheme. An example is a 2019  algorithm  known as OTTER: it performs a fit onto  sum of exponentials  curve for the input data but only uses it to suggest better sample times by finding more highly sloped periods. [ 12 ]


The  area under the effect curve  (AUEC) is an integral of the  effect  of a drug over time, estimated as a previously-established function of concentration. It was proposed to be used instead of AUC in animal-to-human dose translation, as  computer simulation  shows that it could cope better with  half-life  and dosing schedule variations than AUC. This is an example of a  PK/PD model , which combines  pharmacokinetics  and  pharmacodynamics . [ 13 ]


In  pharmacokinetics  and  receptor-ligand kinetics  the  binding potential  (BP) is a combined measure of the density of "available"  neuroreceptors  and the  affinity  of a drug to that neuroreceptor.


Consider a  ligand  receptor binding system. Ligand with a concentration  L  associates with a receptor of concentration or availability  R  to form a ligand-receptor complex with concentration  RL . The binding potential is then the ratio ligand-receptor complex to free ligand at equilibrium and in the limit of L tending to 0, and is given symbol BP:


B
 P
 =

 R
 L

 L

 |

 L
 ≈
 0

 {\displaystyle BP={\frac {RL}{L}}{\bigg |}_{L\approx 0}}


This quantity, originally defined by Mintun, [ 1 ]  describes the capacity of a receptor to bind ligand. It is a limit (L << Ki) of the general receptor association equation:


R
 L
 =

 R
 ∗
 L

 L
 +
 K
 i

 {\displaystyle RL={\frac {R*L}{L+Ki}}}


and is thus also equivalent to:


B
 P
 =

 R

 K

 i

 {\displaystyle BP={\frac {R}{K_{i}}}}


These equations apply equally when measuring the total receptor density or the residual receptor density available after binding to second ligand - availability.


BP is a pivotal measure in the use of  positron emission tomography  (PET) to measure the density of "available" receptors, e.g. to assess the occupancy by drugs or to characterize neuropsychiatric diseases (yet, one should keep in mind that binding potential is a combined measure that depends on receptor density as well as on affinity). An overview of the related methodology is e.g. given in Laruelle et al. (2002). [ 2 ]
Estimating BP with PET usually requires that a reference tissue is available. A reference tissue has negligible receptor density and its distribution volume should be the same as the distribution volume in the target region if all receptors were blocked. Although the BP can be measured in a relatively unbiased way by measuring the whole time course of labelled ligand association and blood radioactivity, this is practically not always necessary. Two other common measures have been derived, which involve assumptions, but result in measures that should correlate with BP:

 B

 P

 1

 {\displaystyle BP_{1}}

  and

 B

 P

 2

 {\displaystyle BP_{2}}

 .


While

 B

 P

 1

 {\displaystyle BP_{1}}

  and

 B

 P

 2

 {\displaystyle BP_{2}}

  are nonambiguous symbols, BP is not. There are many publications in which BP denotes

 B

 P

 2

 {\displaystyle BP_{2}}

 . Generally, if there were no arterial samples ("noninvasive imaging"), BP denotes

 B

 P

 2

 {\displaystyle BP_{2}}

 .


B

 m
 a
 x

 {\displaystyle B_{max}}

 : Total density of receptors =

 R
 +
 R
 L

 {\displaystyle R+RL}

 . In PET imaging, the amount of radioligand is usually very small (L << Ki, see above), thus

 B

 m
 a
 x

 ≈
 R

 {\displaystyle B_{max}\approx R}


k

 3

 {\displaystyle k_{3}}

  and

 k

 4

 {\displaystyle k_{4}}

 : Transfer rate constants from the  two tissue compartment model .


NEW NOTATIONAL CONVENTIONS:
In Innis et al., [ 3 ]  a large group of researchers who are active in this field agreed to a consensus nomenclature for these terms, with the intent of making the literature in this field more transparent to non-specialists.  The convention involves use of the subscripts p for quantities referred to plasma and ND for quantities referred to the free plus nonspecifically bound concentration in brain (NonDisplaceable).  Under the consensus nomenclature, the parameters referred to above as f 1  and BP 1  are now called f p  and BP p , while f 2  and BP 2  are called f ND  and BP ND .


Bioanalysis  is a sub-discipline of  analytical chemistry  covering the  quantitative  measurement of  xenobiotics  (drugs and their  metabolites , and  biological molecules  in unnatural locations or concentrations) and biotics ( macromolecules ,  proteins ,  DNA , large molecule drugs, metabolites) in  biological systems .


Many scientific endeavors are dependent upon accurate quantification of drugs and endogenous substances in biological samples; the focus of bioanalysis in the  pharmaceutical  industry is to provide a quantitative measure of the active drug and/or its metabolite(s) for the purpose of  pharmacokinetics ,  toxicokinetics ,  bioequivalence  and exposure–response (pharmacokinetics/pharmacodynamics studies). Bioanalysis also applies to drugs used for illicit purposes,  forensic  investigations, anti- doping  testing in sports, and environmental concerns.


Bioanalysis was traditionally thought of in terms of measuring small molecule drugs. However, the past twenty years has seen an increase in  biopharmaceuticals  (e.g.  proteins  and  peptides ), which have been developed to address many of the same diseases as small molecules. These larger biomolecules have presented their own unique challenges to quantification. [ 1 ]


The first studies measuring drugs in biological fluids were carried out to determine possible overdosing as part of the new science of forensic medicine/ toxicology .


Initially, nonspecific assays were applied to measuring drugs in biological fluids. These were unable to discriminate between the drug and its metabolites; for example,  aspirin  ( c.  1900 ) and  sulfonamides  (developed in the 1930s) were quantified by the use of  colorimetric  assays.  Antibiotics  were quantified by their ability to inhibit bacterial growth. The 1930s also saw the rise of pharmacokinetics, and as such the desire for more specific assays. [ 2 ]  Modern drugs are more potent, which has required more sensitive bioanalytical assays to accurately and reliably determine these drugs at lower concentrations. This has driven improvements in technology and analytical methods.


Some techniques commonly used in bioanalytical studies include:


The most frequently used techniques are: liquid chromatography coupled with tandem mass spectrometry ( LC–MS/MS ) for 'small' molecules and enzyme-linked immunosorbent assay ( ELISA ) for macromolecules. [ citation needed ]


The bioanalyst deals with complex biological samples containing the analyte alongside a diverse range of chemicals that can have an adverse impact on the accurate and precise quantification of the analyte. As such, a wide range of techniques are applied to extract the analyte from its matrix. These include:


Bioanalytical laboratories often deal with large numbers of samples, for example resulting from clinical trials. As such, automated sample preparation methods and liquid-handling robots are commonly employed to increase efficiency and reduce costs.


There are several national and international bioanalytical organisations active throughout the world. Often they are part of a bigger organisation, e.g. Bioanalytical Focus Group and Ligand Binding Assay Bioanalytical Focus Group, which are both within the American Association of Pharmaceutical Scientists (AAPS) and FABIAN, a working group of the Analytical Chemistry Section of the  Royal Netherlands Chemical Society . The  European Bioanalysis Forum  (EBF), on the other hand, is independent of any larger society or association.


Bioequivalence  is a term in  pharmacokinetics  used to assess the expected  in vivo  biological equivalence of two proprietary preparations of a drug. If two products are said to be bioequivalent it means that they would be expected to be, for all intents and purposes, the same.


One article defined bioequivalence by stating that, "two pharmaceutical products are bioequivalent if they are pharmaceutically equivalent and their  bioavailabilities  (rate and extent of availability) after administration in the same  molar dose  are similar to such a degree that their effects, with respect to both  efficacy  and safety, can be expected to be essentially the same. Pharmaceutical equivalence implies the same amount of the same active substance(s), in the same dosage form, for the same route of administration and meeting the same or comparable standards." [ 1 ]


For  The World Health Organization  (WHO) "two pharmaceutical products are bioequivalent if they are pharmaceutically equivalent or pharmaceutical alternatives, and their bioavailabilities, in terms of rate (Cmax and tmax) and extent of absorption (area under the curve), after administration of the same molar dose under the same conditions, are similar to such a degree that their effects can be expected to be essentially the same". [ 2 ]


The  United States   Food and Drug Administration  (FDA) has defined bioequivalence as, "the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study." [ 3 ]


In determining bioequivalence between two products such as a commercially available Branded product and a potential to-be-marketed  Generic product ,  pharmacokinetic  studies are conducted whereby each of the preparations are administered in a  cross-over study  (sometimes parallel study, when a cross-over study is not feasible) to volunteer subjects, generally healthy individuals but occasionally in patients.  Serum/plasma  samples are obtained at prescribed times and assayed for parent drug (or occasionally  metabolite ) concentration. Occasionally, blood concentration levels are neither feasible or possible to compare the two products (e.g. inhaled  corticosteroids ), then  pharmacodynamic  endpoints rather than pharmacokinetic endpoints (see below) are used for comparison. For a pharmacokinetic comparison, the plasma concentration data are used to assess key pharmacokinetic parameters such as area under the curve (AUC), peak concentration ( C max ), time to peak concentration ( t max ), and absorption lag time ( t lag ). Testing should be conducted at several different doses, especially when the drug displays non-linear pharmacokinetics.


In addition to data from bioequivalence studies, other data may need to be submitted to meet  regulatory requirements  for bioequivalence. Such evidence may include:


The World Health Organization considers two formulation bioequivalent if the 90% confidence interval for the ratio multisource (generic) product/comparator lie within 80.00–125.00% acceptance range for AUC 0–t  and C max . For high variable finished pharmaceutical products, the applicable acceptance range for C max  can be expanded (up to 69.84–143.19%). [ 4 ]


In  Australia , the  Therapeutics Goods Administration  (TGA) considers preparations to be bioequivalent if the 90%  confidence intervals  (90% CI) of the rate ratios, between the two preparations, of  C max  and AUC lie in the range 0.80–1.25.  T max  should also be similar between the products. [ 1 ]


There are tighter requirements for drugs with a narrow  therapeutic index  and/or saturable metabolism – thus no generic products exist on the Australian market for  digoxin  or  phenytoin  for instance.


According to regulations applicable in the  European Economic Area [ 5 ]  two medicinal products are bioequivalent if they are pharmaceutically equivalent or pharmaceutical alternatives and if their bioavailabilities after administration in the same molar dose are similar to such a degree that their effects, with respect to both efficacy and safety, will be essentially the same. This is considered demonstrated if the 90%  confidence intervals  (90% CI) of the ratios for AUC 0–t  and  C max  between the two preparations lie in the range 80–125%.


The FDA considers two products bioequivalent if the 90% CI of the relative mean C max , AUC (0–t)  and AUC (0–∞)  of the test (e.g. generic formulation) to reference (e.g. innovator brand formulation) should be within 80% to 125% in the fasting state. Although there are a few exceptions, generally a bioequivalent comparison of Test to Reference formulations also requires administration after an appropriate meal at a specified time before taking the drug, a so-called "fed" or "food-effect" study. A food-effect study requires the same statistical evaluation as the fasting study, described above. [ 3 ]


There were no requirements for bioequivalence in generic medications in China until the 2016  Opinion on Conducting Consistent Evaluation of the Quality and Efficacy of Generic Drugs  ( 关于开展仿制药质量和疗效一致性评价的意见 ), which established basic rules for future bioequivalence work. Since July 2020, all newly-approved generics must pass bioequivalence checks; previous drugs may apply to be checked. Since 2019, National Centralized Volume-Based Procurement uses "passes generic-consistency evalulation" as one of the bidding criteria. [ 7 ]


The Chinese definition of "bioequivalence" entails having the test drug's geometric mean C max , AUC (0–t) , and AUC (0–∞)  fall into 80%–125% of the reference drug in both fasting and fed states. The reference drug should be preferably the original brand-name drug, then (if not available) an internationally-recognized generic approved by a developed country, then (if still not available) an internationally-recognized generic approved domestically – this is to avoid deviation from the original drug by serial use of generics as reference. If pharmacokinetic values such as C max  do not apply to the type of drug (e.g. if the drug is not absorbed orally), comparisons can be made using other means such as  dose-response curves . [ 7 ]


According to Wei et al. (2022), the Consistency Evaluation Policy increased R&D spending for Chinese pharmaceutical companies, especially among private and high-yielding ones. [ 8 ]  Liu et al. (2023) argues that the Policy increased the innovation quality of the Chinese pharmaceutical industry. [ 9 ]


While the FDA maintains that approved generic drugs are equivalent to their branded counterparts, bioequivalence problems have been reported by physicians and patients for many drugs. [ 10 ]  Certain classes of drugs are suspected to be particularly problematic because of their chemistry. Some of these include  chiral drugs , poorly absorbed drugs, and cytotoxic drugs. In addition, complex delivery mechanisms can cause bioequivalence variances. [ 10 ]  Physicians are cautioned to avoid switching patients from branded to generic, or between different generic manufacturers, when prescribing anti-epileptic drugs,  warfarin , and  levothyroxine . [ 11 ]


Major issues were raised in the verification of bioequivalence when multiple generic versions of FDA-approved generic drug were found not to be equivalent in efficacy and side effect profiles. [ 12 ]  In 2007, two providers of consumer information on nutritional products and supplements,  ConsumerLab.com  and The People's Pharmacy, released the results of comparative tests of different brands of bupropion. [ 13 ]  The People's Pharmacy received multiple reports of increased side effects and decreased efficacy of generic bupropion, which prompted it to ask ConsumerLab.com to test the products in question. The tests showed that some generic versions of Wellbutrin XL 300 mg didn't perform the same as the brand-name pill in laboratory tests. [ 14 ]  The FDA investigated these complaints and concluded that the generic version is equivalent to Wellbutrin XL in regard to bioavailability of bupropion and its main active metabolite hydroxybupropion. The FDA also said that coincidental natural mood variation is the most likely explanation for the apparent worsening of depression after the switch from Wellbutrin XL to Budeprion XL. [ 15 ]  After several years of denying patient reports, in 2012 the FDA reversed this opinion, announcing that "Budeprion XL 300 mg fails to demonstrate therapeutic equivalence to Wellbutrin XL 300 mg." [ 16 ]  The FDA did not test the bioequivalence of any of the other generic versions of Wellbutrin XL 300 mg, but requested that the four manufacturers submit data on this question to the FDA by March 2013. As of October 2013, the FDA has made determinations on the formulations from some manufacturers not being bioequivalent. [ 17 ]


In 2004,  Ranbaxy  was revealed to have been falsifying data regarding the generic drugs they were manufacturing. As a result, 30 products were removed from US markets and Ranbaxy paid $500 million in fines. The FDA investigated many Indian drug manufacturers after this was discovered, and as a result at least 12 companies have been banned from shipping drugs to the US. [ 11 ]


In 2017, The  European Medicines Agency  recommended suspension of a number of nationally approved medicines for which bioequivalence studies were conducted by Micro Therapeutic Research Labs in India, due to inspections identifying misrepresentation of study data and deficiencies in documentation and data handling. [ 18 ]


Biological half-life  ( elimination half-life ,  pharmacological half-life ) is the time taken for concentration of a  biological substance  (such as a  medication ) to decrease from its maximum  concentration  ( C max ) to half of C max  in the  blood plasma . [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]  It is denoted by the abbreviation

 t

 1
 2

 {\displaystyle t_{\frac {1}{2}}}

 . [ 2 ] [ 4 ]


This is used to measure the removal of things such as  metabolites ,  drugs , and  signalling molecules  from the body. Typically, the biological half-life refers to the body's natural  detoxification  (cleansing) through  liver metabolism  and through the  excretion  of the measured substance through the kidneys and intestines. This concept is used when the rate of removal is roughly  exponential . [ 6 ]


In a medical context, half-life explicitly describes the time it takes for the  blood plasma  concentration of a substance to halve ( plasma half-life ) its steady-state when circulating in the full blood of an  organism . This measurement is useful in medicine,  pharmacology  and  pharmacokinetics  because it helps determine how much of a drug needs to be taken and how frequently it needs to be taken if a certain average amount is needed constantly. By contrast, the stability of a substance in plasma is described as  plasma stability.  This is essential to ensure accurate analysis of drugs in plasma and for  drug discovery .


The relationship between the biological and plasma half-lives of a substance can be complex depending on the substance in question, due to factors including accumulation in tissues,  protein binding , active metabolites, and receptor interactions. [ 7 ]


The biological half-life of water in a human is about 7 to 14 days. It can be altered by behavior. Drinking large amounts of  alcohol  will reduce the biological half-life of water in the body. [ 8 ] [ 9 ]  This has been used to decontaminate patients who are internally contaminated with  tritiated water . The basis of this decontamination method is to increase the rate at which the water in the body is replaced with new water.


The removal of  ethanol  (drinking alcohol) through oxidation by  alcohol dehydrogenase  in the  liver  from the human body is limited. Hence the removal of a large concentration of alcohol from  blood  may follow  zero-order kinetics . Also the rate-limiting steps for one substance may be in common with other substances. For instance, the blood alcohol concentration can be used to modify the biochemistry of  methanol  and  ethylene glycol . In this way the oxidation of methanol to the  toxic   formaldehyde  and  formic acid  in the human body can be prevented by giving an appropriate amount of  ethanol  to a person who has  ingested  methanol. Methanol is very toxic and causes  blindness  and death. A person who has ingested  ethylene glycol  can be treated in the same way. Half life is also relative to the subjective metabolic rate of the individual in question.


Active metabolite ( N-desalkylflurazepam ): 47–100 hours [ 15 ]


8–15 hours (higher doses) [ 16 ]


in rare cases up to 8 days [ 17 ]


Active metabolite ( nordazepam ): 30–200 hours [ 18 ]


Active lipophilic metabolite ( norfluoxetine ): 4–16 days [ 23 ]


The biological half-life of  caesium  in humans is between one and four months. This can be shortened by feeding the person  prussian blue . The prussian blue in the digestive system acts as a solid  ion exchanger  which absorbs the caesium while releasing  potassium  ions.


For some substances, it is important to think of the human or animal body as being made up of several parts, each with its own affinity for the substance, and each part with a different biological half-life ( physiologically-based pharmacokinetic modelling ). Attempts to remove a substance from the whole organism may have the effect of increasing the burden present in one part of the organism. For instance, if a person who is contaminated with lead is given  EDTA  in a  chelation therapy , then while the rate at which lead is lost from the body will be increased, the lead within the body tends to relocate into the  brain  where it can do the most harm. [ 28 ]


Some substances may have different half-lives in different parts of the body. For example,  oxytocin  has a  half-life  of typically about three minutes in the blood when given  intravenously . Peripherally administered (e.g. intravenous) peptides like oxytocin cross the  blood-brain-barrier  very poorly, although very small amounts (< 1%) do appear to enter the  central nervous system  in humans when given via this route. [ 31 ]  In contrast to peripheral administration, when administered  intranasally  via a nasal spray, oxytocin reliably crosses the  blood–brain barrier  and exhibits  psychoactive  effects in humans. [ 32 ] [ 33 ]  In addition, unlike the case of peripheral administration, intranasal oxytocin has a central duration of at least 2.25 hours and as long as 4 hours. [ 34 ] [ 35 ]  In likely relation to this fact, endogenous oxytocin concentrations in the brain have been found to be as much as 1000-fold higher than peripheral levels. [ 31 ]


Half-times apply to processes where the elimination rate is exponential. If

 C
 (
 t
 )

 {\displaystyle C(t)}

  is the concentration of a substance at time

 t

 {\displaystyle t}

 , its time dependence is given by


where  k  is the  reaction rate constant . Such a decay rate arises from a  first-order reaction  where the rate of elimination is proportional to the amount of the substance: [ 39 ]


The half-life for this process is [ 39 ]


Alternatively, half-life is given by


where  λ z  is the slope of the terminal phase of the time–concentration curve for the substance on a semilogarithmic scale. [ 40 ] [ 41 ]


Half-life is determined by  clearance  (CL) and  volume of distribution  (V D ) and the relationship is described by the following equation:


In clinical practice, this means that it takes 4 to 5 times the half-life for a drug's serum concentration to reach steady state after regular dosing is started, stopped, or the dose changed.  So, for example, digoxin has a half-life (or t  1 / 2  ) of 24–36 h; this means that a change in the dose will take the best part of a week to take full effect. For this reason, drugs with a long half-life (e.g.,  amiodarone , elimination t  1 / 2   of about 58 days) are usually started with a  loading dose  to achieve their desired clinical effect more quickly.


Many drugs follow a biphasic elimination curve — first a steep slope then a shallow slope:


The longer half-life is called the  terminal half-life  and the half-life of the largest component is called the  dominant half-life. [ 39 ]  For a more detailed description see  Pharmacokinetics § Multi-compartmental models .


Blood–gas partition coefficient , also known as  Ostwald coefficient for blood–gas , [ 1 ]  is a term used in  pharmacology  to describe the solubility of inhaled  general anesthetics  in blood. [ 2 ]  According to  Henry's law , the ratio of the concentration in blood to the concentration in gas that is in contact with that blood, when the  partial pressure  in both compartments is equal, is nearly constant at sufficiently low concentrations.  The partition coefficient is defined as this ratio and, therefore, has no units. The concentration of the anesthetic in blood includes the portion that is undissolved in plasma and the portion that is dissolved (bound to  plasma proteins ). The more  soluble  the inhaled anesthetic is in blood compared to in air, the more it binds to plasma proteins in the blood and the higher the blood–gas  partition coefficient .


It is inversely related to  induction rate . Induction rate is defined as the speed at which an agent produces anesthesia. The higher the  blood:gas partition coefficient , the slower the rate of induction.


Newer anesthetics (such as  desflurane ) typically have smaller blood–gas partition coefficients than older ones (such as  ether ); this leads to faster onset of anesthesia and faster emergence from anesthesia once application of the anesthetic is stopped, which may be preferable in certain clinical scenarios. [ 3 ] [ 4 ]  If an anesthetic has a high coefficient, then a large amount of it will have to be taken up in the body's blood before being passed on to the fatty (lipid) tissues of the brain where it can exert its effect.


The potency of an anesthetic is associated with its lipid solubility, which is measured by its oil/gas partition coefficient. [ 5 ]


Minimum alveolar concentration (MAC) is defined as the alveolar concentration of anesthetic gas that prevents a movement response in half of subjects undergoing a painful (surgical) stimulus; simplified, it is the exhaled gas concentration required to produce anaesthetic effects –  an inverse indicator of anesthetic gas potency.


The  blood–brain barrier  ( BBB ) is a highly selective  semipermeable  border of  endothelial cells  that regulates the transfer of solutes and chemicals between the  circulatory system  and the  central nervous system , thus protecting the  brain  from harmful or unwanted substances in the  blood . [ 1 ]  The blood–brain barrier is formed by endothelial cells of the  capillary wall ,  astrocyte  end-feet ensheathing the capillary, and  pericytes  embedded in the capillary  basement membrane . [ 2 ]  This system allows the passage of some small molecules by  passive diffusion , as well as the selective and active transport of various nutrients, ions, organic anions, and macromolecules such as glucose and  amino acids  that are crucial to neural function. [ 3 ]


The blood–brain barrier restricts the passage of  pathogens , the diffusion of  solutes  in the blood, and  large  or  hydrophilic  molecules into the  cerebrospinal fluid , while allowing the diffusion of  hydrophobic  molecules (O 2 , CO 2 , hormones) and small non-polar molecules. [ 4 ] [ 5 ]  Cells of the barrier actively transport  metabolic  products such as glucose across the barrier using specific  transport proteins . [ 6 ]  The barrier also restricts the passage of peripheral immune factors, like signaling molecules, antibodies, and immune cells, into the central nervous system, thus insulating the brain from damage due to peripheral immune events. [ 7 ]


Specialized brain structures participating in sensory and secretory integration within brain  neural circuits —the  circumventricular organs  and  choroid plexus —have in contrast highly permeable capillaries. [ 8 ]


The BBB results from the selectivity of the  tight junctions  between the endothelial cells of brain capillaries, restricting the passage of solutes. [ 1 ]   At the interface between blood and the brain, endothelial cells are adjoined continuously by these tight junctions, which are composed of smaller subunits of  transmembrane proteins , such as  occludin ,  claudins  (such as  Claudin-5 ),  junctional adhesion molecule  (such as JAM-A). [ 6 ]  Each of these tight junction proteins is stabilized to the endothelial cell membrane by another protein complex that includes scaffolding proteins such as  tight junction protein 1  (ZO1) and associated proteins. [ 6 ]


The BBB is composed of endothelial cells restricting passage of substances from the blood more selectively than endothelial cells of capillaries elsewhere in the body. [ 9 ]   Astrocyte  cell projections called astrocytic feet (also known as " glia limitans ") surround the endothelial cells of the BBB, providing biochemical support to those cells. [ 10 ]  The BBB is distinct from the quite similar  blood-cerebrospinal fluid barrier , which is a function of the choroidal cells of the  choroid plexus , and from the  blood-retinal barrier , which can be considered a part of the whole realm of such barriers. [ 11 ]


Not all vessels in the human brain exhibit BBB properties. Some examples of this include the  circumventricular organs , the roof of the third and fourth  ventricles , capillaries in the pineal gland on the roof of the  diencephalon  and the  pineal gland . The pineal gland secretes the hormone  melatonin  "directly into the systemic circulation", [ 12 ]  thus melatonin is not affected by the blood–brain barrier. [ 13 ]


The BBB appears to be functional by the time of birth.  P-glycoprotein , a  transporter , exists already in the embryonal endothelium. [ 14 ]


Measurement of brain uptake of various blood-borne solutes showed that newborn endothelial cells were functionally similar to those in adults, [ 15 ]  indicating that a selective BBB is operative at birth.


In mice, Claudin-5 loss during development is lethal and results in size-selective (up to 742Da) loosening of the BBB. [ 16 ]  Mosaic deletion of claudin-5 in adult endothelial cells (in mice) reveals BBB leakage up to 10kDa molecule 6 days after deletion of claudin-5 and lethality after 10 days after deletion demonstrating a critical role of Claudin-5 in adult BBB. [ 17 ]


The blood–brain barrier acts effectively to protect brain tissue from circulating  pathogens  and other potentially toxic substances. [ 18 ]  Accordingly,  blood-borne infections  of the brain are rare. [ 1 ]   Infections  of the brain that do occur are often difficult to treat.  Antibodies  are too large to cross the blood–brain barrier, and only certain  antibiotics  are able to pass. [ 19 ]  In some cases, a drug has to be administered directly into the cerebrospinal fluid where it can enter the brain by crossing the  blood-cerebrospinal fluid barrier . [ 20 ] [ 21 ]


Circumventricular organs  (CVOs) are individual structures located adjacent to the  fourth ventricle  or  third ventricle  in the brain, and are characterized by dense capillary beds with  permeable  endothelial cells unlike those of the blood–brain barrier. [ 22 ] [ 23 ]  Included among CVOs having highly permeable capillaries are the  area postrema ,  subfornical organ ,  vascular organ of the lamina terminalis ,  median eminence ,  pineal gland , and three lobes of the   pituitary gland . [ 22 ] [ 24 ]


Permeable capillaries of the sensory CVOs (area postrema, subfornical organ, vascular organ of the lamina terminalis) enable rapid detection of circulating signals in systemic blood, while those of the secretory CVOs (median eminence, pineal gland, pituitary lobes) facilitate transport of brain-derived signals into the circulating blood. [ 22 ] [ 23 ]  Consequently, the CVO permeable capillaries are the point of bidirectional blood–brain communication for  neuroendocrine  function. [ 22 ] [ 24 ] [ 25 ]


The border zones between brain tissue "behind" the blood–brain barrier and zones "open" to blood signals in certain CVOs contain specialized hybrid capillaries that are leakier than typical brain capillaries, but not as permeable as CVO capillaries. Such zones exist at the border of the area postrema— nucleus tractus solitarii  (NTS), [ 26 ]  and median eminence— hypothalamic   arcuate nucleus . [ 25 ] [ 27 ]  These zones appear to function as rapid transit regions for brain structures involved in diverse neural circuits—like the NTS and arcuate nucleus—to receive blood signals which are then transmitted into neural output. [ 25 ] [ 26 ]  The permeable capillary zone shared between the median eminence and hypothalamic arcuate nucleus is augmented by wide pericapillary spaces, facilitating bidirectional flow of solutes between the two structures, and indicating that the median eminence is not only a secretory organ, but may also be a sensory organ. [ 25 ] [ 27 ]


The blood–brain barrier is formed by the brain capillary endothelium and excludes from the brain 100% of large-molecule neurotherapeutics and more than 98% of all small-molecule drugs. [ 28 ]  Overcoming the difficulty of delivering therapeutic agents to specific regions of the brain presents a major challenge to treatment of most brain disorders. [ 29 ] [ 30 ]  In its neuroprotective role, the blood–brain barrier functions to hinder the delivery of many potentially important diagnostic and therapeutic agents to the brain. Therapeutic molecules and antibodies that might otherwise be effective in diagnosis and therapy do not cross the BBB in adequate amounts to be clinically effective. [ 29 ]  To overcome this problem some peptides able to naturally cross the BBB have been widely investigated as a drug delivery system. [ 31 ]


Mechanisms for drug targeting in the brain involve going either "through" or "behind" the BBB. Modalities for  drug delivery to the brain  in  unit doses  through the BBB entail its disruption by  osmotic  means, or biochemically by the use of vasoactive substances, such as  bradykinin , [ 32 ]  or even by localized exposure to  high-intensity focused ultrasound (HIFU) . [ 33 ]


Other methods used to get through the BBB may entail the use of endogenous transport systems, including carrier-mediated transporters, such as glucose and amino acid carriers, receptor-mediated  transcytosis  for  insulin  or  transferrin , and the blocking of  active efflux transporters  such as  p-glycoprotein . [ 29 ]  Some studies have shown that  vectors  targeting BBB transporters, such as the  transferrin receptor , have been found to remain entrapped in brain endothelial cells of capillaries, instead of being ferried across the BBB into the targeted area. [ 29 ] [ 34 ]


The brain can be targeted non-invasively via the nasal passage. The drugs that remain in the passage after mucociliary clearance, enter the brain via three pathways: (1) Olfactory nerve-olfactory bulb-brain; (2) Trigeminal nerve-brain; and (3) Lungs/ Gastrointestinal tract-blood–brain  [ 35 ]  The first and second methods involve the nerves, so they use the neuronal pathway and the third is via systemic circulation. However, these methods are less efficient to deliver drugs as they are indirect methods.


Nanotechnology  is under preliminary research for its potential to facilitate the transfer of drugs across the BBB. [ 29 ] [ 36 ] [ 37 ]  Capillary endothelial cells and associated  pericytes  may be abnormal in tumors and the blood–brain barrier may not always be intact in brain tumors. [ 37 ]  Other factors, such as  astrocytes , may contribute to the resistance of brain tumors to therapy using nanoparticles. [ 38 ]  Fat soluble molecules less than 400  daltons  in mass can freely diffuse past the BBB through  lipid  mediated passive diffusion. [ 39 ]


The blood–brain barrier may become damaged in certain  neurological diseases , as indicated by  neuroimaging  studies of  Alzheimer's disease ,  amyotrophic lateral sclerosis ,  epilepsy , ischemic stroke, [ 18 ] [ 40 ] [ 41 ] [ 42 ]  and  brain trauma , [ 29 ]  and in  systemic diseases , such as  liver failure . [ 1 ]  Effects such as impaired glucose transport and endothelial degeneration may lead to metabolic dysfunction within the brain, and an increased permeability of the BBB to  proinflammatory  factors, potentially allowing antibiotics and  phagocytes  to move across the BBB. [ 1 ] [ 29 ]  However, in many neurodegenerative diseases, the exact cause and pathology remains unknown. It is still unclear whether the BBB dysfunction in the disease is a causative agent, a result of the disease, or somewhere in the middle.


A 1898 study observed that low-concentration " bile salts " failed to affect behavior when injected into the blood of animals. Thus, in theory, the salts failed to enter the brain. [ 43 ]


Two years later,  Max Lewandowsky  may have been the first to coin the term "blood–brain barrier" in 1900, referring to the hypothesized semipermeable membrane. [ 44 ]  There is some debate over the creation of the term  blood–brain barrier  as it is often attributed to Lewandowsky, but it does not appear in his papers. The creator of the term may have been  Lina Stern . [ 45 ]  Stern was a Russian scientist who published her work in Russian and French. Due to the language barrier between her publications and English-speaking scientists, this could have made her work a lesser-known origin of the term.


All the while,  bacteriologist   Paul Ehrlich  was studying  staining , a procedure that is used in many  microscopy studies  to make fine biological structures visible using chemical dyes. [ 46 ]  As Ehrlich injected some of these dyes (notably the  aniline dyes  that were then widely used), the dye stained all of the  organs  of some kinds of animals except for their brains. [ 46 ]  At that time, Ehrlich attributed this lack of staining to the brain simply not picking up as much of the dye. [ 44 ]


However, in a later experiment in 1913,  Edwin Goldmann  (one of Ehrlich's students) injected the dye directly into the  cerebrospinal fluid  of animal brains. He found then the brains did become dyed, but the rest of the body did not, demonstrating the existence of a compartmentalization between the two. At that time, it was thought that the blood vessels themselves were responsible for the barrier, since no obvious membrane could be found.


A  caffeinated alcoholic drink  is a  drink  that contains both  alcohol  (also known formally as  ethanol ) and a significant amount of  caffeine . Caffeine, a  stimulant , masks some of the  depressant  effects of alcohol. [ 1 ]  However, in 2010 and 2011, this type of drink faced criticism for posing health risks to its drinkers. In some places there is a ban on caffeinated alcoholic drinks.


Sometimes, caffeinated alcoholic drinks are made by mixing existing caffeinated drinks ( coffee ,  energy drinks ,  cola ) with alcoholic drinks.


The main ingredients in caffeinated alcoholic drinks are  alcohol  and  caffeine . The caffeine is often added by ingredients like  energy drinks ,  coffee ,  tea , or  dark chocolate . A well-known and popular such drink is  Irish coffee .


In 2010, the FDA advised that caffeinated alcoholic beverages should not be consumed because of the counteracting effects of caffeine and alcohol. The FDA posited that caffeine often causes consumers to drink more than they normally would because caffeine can mask some of the sensory cues individuals might normally rely on to determine their level of intoxication. This masking of intoxication then leads individuals to engage in behaviors that they would otherwise avoid if they understood their true level of intoxication. [ 3 ]  However, research has not fully supported this tenet. For example, one study found that Australian students thought they were more intoxicated when mixing caffeine with alcohol than when consuming alcohol on its own for every level of blood alcohol content. [ citation needed ]  Consuming high levels of caffeine was associated with more alcohol-related consequences than when consuming alcohol on its own, even when consuming relatively little alcohol. It may be that caffeine causes individuals to focus on the stimulant effects of the intoxication, which have been associated with greater perceived intoxication than the depressant effects of alcohol. [ 4 ]


It is inferred that caffeinated alcoholic drinks cause one to act in ways that would be less likely if one were drinking non-caffeinated alcoholic drinks.


Universities have conducted studies to compare the outcomes of the consumption of regular alcoholic drinks and of caffeinated alcoholic drinks:


In  Australia , the Ministerial Council on Drug Strategy is considering regulation to address the growing concerns over the drinks.  [ citation needed ]


In  Canada , regulations restrict the manufacture and sale of caffeinated alcoholic drinks unless the caffeine comes from a natural ingredient such as guarana; caffeine as an ingredient cannot be directly added to an alcoholic drink. [ 9 ]


In  Mexico , caffeinated alcoholic drinks cannot be sold in bars or nightclubs. [ citation needed ]


Several  Scottish  politicians and social activists have singled out the a caffeinated alcoholic drink  Buckfast Tonic Wine  as being particularly responsible for crime, disorder, and general social deprivation in certain communities. There have been numerous calls for the drink to be banned (either throughout the country or in certain areas or shops), made more expensive to dissuade people from buying the product, or sold in plastic bottles to reduce  glassing  incidents.  Helen Liddell , former  Secretary of State for Scotland , called for the wine to be banned. [ 10 ]  In 2005, Scottish Justice Minister  Cathy Jamieson  suggested that retailers should stop selling the wine. [ 11 ]  All of these initiatives have been countered by lawyers acting for Buckfast distributors, J. Chandler & Company, in  Andover . [ 10 ] [ 12 ]


In January 2010, a  BBC  investigation revealed that  Buckfast Tonic Wine  had been mentioned in 5,638 crime reports in the  Strathclyde  area of Scotland from 2006 to 2009, equating to an average of three per day.  In 2017, Scottish Police reported there had been 6,500 crimes related to the drink in the previous two years. [ 13 ]


The adverse effects of caffeinated alcoholic drinks have led to increased regulation.  Under the  Federal Food, Drug, and Cosmetic Act , a substance intentionally added to food (such as caffeine in alcoholic drinks) is deemed "unsafe" and is unlawful unless its particular use has been approved by FDA (Food and Drug Administration) regulation. The substance is subject to a prior sanction until the substance is Generally Regarded As Safe ( GRAS ). [ 14 ]   In order for a substance to be characterized as GRAS, there must be sufficient evidence to prove its safety; this evidence should be generally known and accepted by qualified professionals. [ 9 ]   The FDA did not approve the use of caffeine in alcoholic drinks, and thus the drinks cannot be legally marketed.  As a result, the FDA sent letters to four manufacturers of caffeinated alcoholic drinks (Phusion Projects, Charge Beverages Corporation, New Century Brewing Company, and United Brands Company, Inc.) to alert them that the agency would be considering whether caffeine can lawfully be added to alcoholic drinks. [ 9 ]  These letters also gave the manufacturers fifteen days to stop the addition of caffeine to the alcoholic drinks or to stop selling the drinks altogether.


The  Federal Trade Commission  (FTC) also took action against the four companies, warning that their marketing tactics might violate federal law and urging them to take swift and appropriate steps to protect consumers. [ 15 ]


CDC  recommends against the combination of alcohol and caffeine. [ 16 ]


The  Dietary Guidelines for Americans  recommend avoidance of concomitant consumption of alcohol and caffeine, as this may lead to increased alcohol consumption, with a higher risk of alcohol-associated injury.


In 2009, the FDA required several manufacturers to remove caffeine from their  alcopops  including City Brewing of La Crosse, Wisc. which makes Hard Wired and 24/7; Gaamm Imports Inc., of Deerfield Beach, Fla. which makes Booya Espresso Silver Tequila and Caffeine, and United Brands Co., maker of  Joose , Max Vibe, Max Fury, Max Live and 3Sum. Anheuser-Busch and Miller have stopped making their caffeinated alcoholic drinks,  Tilt ,  Bud Extra  and  Sparks . [ 17 ]   Rhythm  was also banned 2009.


The day before the FDA sent out the warning letters, Phusion Projects (now  Four Loko ), a five-year-old Chicago company, said it would stop putting caffeine in the drinks and put a non-caffeinated version of the drink on the market in December 2010.  In a statement, the company's founders said that they still believed it was safe to blend caffeine and alcohol but wanted to cooperate with regulators. [ 15 ]  The FDA continues work with Phusion Projects and other manufacturers to assure their products meet safety standards. [ 3 ]


Targeted drug delivery  is one of many ways researchers seek to improve drug delivery systems' overall efficacy, safety, and delivery. Within this medical field is a special reversal form of  drug delivery  called chemotactic drug targeting. [ 1 ] [ 2 ]  By using chemical agents to help guide a drug carrier to a specific location within the body, this innovative approach seeks to improve precision and control during the drug delivery process, decrease the risk of toxicity, and potentially lower the required medical dosage needed. [ 2 ] [ 3 ] [ 4 ] [ 5 ]  The general components of the conjugates are designed as follows: (i) carrier – regularly possessing promoter effect also on internalization into the cell; (ii) chemotactically active ligands acting on the target cells; (iii) drug to be delivered in a selective way and (iv) spacer sequence which joins drug molecule to the carrier and due to it enzyme labile moiety makes possible the intracellular compartment specific release of the drug. Careful selection of chemotactic component of the ligand not only the  chemoattractant  character could be expended, however,  chemorepellent  ligands are also valuable as they are useful to keep away cell populations degrading the conjugate containing the drug. In a larger sense, chemotactic drug-targeting has the potential to improve cancer, inflammation, and arthritis treatment by taking advantage of the difference in environment between the target site and its surroundings. [ 6 ] [ 7 ] [ 8 ]  Therefore, this Wikipedia article aims to provide a brief overview of chemotactic drug targeting, the principles behind the approach, possible limitations and advantages, and its application to cancer and inflammation.


In general terms,  chemotaxis  is a biological process where living entities, such as cells or organisms, detect, maneuver, and react in response to a chemical signal in their environment. [ 1 ]  Such a phenomenon is critical for many biological processes, including but not limited to wound healing, detection of food, and avoidance of many toxins. [ 2 ]   Chemotaxis  also plays an essential role in several diseases, such as tumor metastasis, the recruitment of T-lymphocytes during inflammation, and HIV-1 entry into T cells. [ 6 ] [ 9 ] [ 10 ]  At the core of  chemotaxis  are specialized sensory cells called chemoreceptors. These cells allow an organism to detect chemical molecules within its environment and respond accordingly. Such chemical molecules are either known as chemoattractants or chemorepellents, which play a crucial role in attracting or repelling the organism towards or away from the source of the chemical signal, respectively. Thus, with this natural process of chemotaxis in mind, researchers have sought to apply the same phenomenon to  targeted drug delivery , a medical technique aimed at delivering drugs to a specific cell, tissue, or organ within the body while minimizing its disruptive effects on healthy tissue. [ 4 ]  By using both chemotaxes to help guide the drug delivery process, researchers aim to reduce toxicity by avoiding healthy tissues, improve drug efficacy by focusing only on the intended site, and decrease drug dosage by delivering the directly rather than throughout the whole body. [ 3 ] [ 11 ]


Chemotactic drug delivery systems are an emerging field of drug delivery that aims to apply the natural phenomenon of chemotaxis in guiding and delivering a drug to a specific tissue or cell within the body. Thus, similar to how organisms use chemotaxis, researchers have designed drug delivery systems to detect, maneuver, and react to chemical molecules released by a desired cell or its surrounding area.


Recent progress in the field of  microfluidics  has led to the development of microdroplets, a new drug-delivery system that uses uniform droplets to deliver drugs to specific locations within the body. [ 2 ] [ 12 ]  These microdroplets allow researchers to load drugs during the polymerization step of their formation and provide variations in porosity, which can control the time it takes to release a therapeutic payload. [ 13 ]  Thus, by using the natural process of chemotaxis, researchers aim to guide these tiny droplets by using chemical gradients released by a specific cell, tissue, or organ within the body. [ 2 ] [ 4 ] [ 12 ]  In fact, a few examples of microdroplet systems that use chemotaxis are self-propelling, ionic liquid-based, and synthetic base. [ 2 ] [ 12 ]  These microdroplet-based drug delivery systems offer several advantages over traditional drug delivery methods, which are talked about later in the advantage and limitations subsection of this article. Overall, the development of microdroplet-based drug delivery systems using the phenomenon of chemotaxis is just one of may avenues to potentially revolutionize the field of medicine and targeted drug delivery. [ 14 ]


Another drug delivery system that has shown potential for chemotactic applicability is protocells. [ 15 ]  In general, protocells are artificial cells that mimic living cells but cannot reproduce and have genetic mutations like living cells do. [ 15 ]  Moreover, protocells combine the advantages of liposomes with that of mesoporous silica nanoparticles. [ 16 ]  These advantages include but are not limited to stability, large capacity for various cargos, low toxicity, immunogenicity, and the ability to circulate the blood for long periods. [ 16 ]  Thus, researchers aim to create a tunable chemotactic protocell that can move towards or away from a chemical signal. [ 17 ] [ 18 ]  In fact, researchers have devised a way to use the enzymes catalase, urease, and ATPase to move the protocell closer or further away from the reactant, giving them direction and movement control of these protocells. [ 17 ] [ 18 ]  Overall, the development of chemotactic controlled protocols holds great promise for the targeted delivery of drugs to specific areas of the body, potentially increasing treatment efficacy while minimizing side effects. However, more research is needed to fully understand the capabilities and limitations of protocells as drug delivery systems and optimize their design and functionality for specific applications.


Finally, biological and bio-hybrid drug carriers have shown potential for chemotactic applications. In general, these systems are inspired by  microorganisms  or cells to help design drug delivery systems that mimic their surface, shape, texture, and movement. [ 4 ] [ 19 ]  One phenomenon that has become increasingly popular in improving the movement and release of  bio-hybrid  drug carriers is that of  chemotaxis . Indeed, thanks to their natural chemotactic sensing property, bacteria can be used to locate a tumor, carry a therapeutic payload to the site, and release that drug in a controlled manner. [ 4 ]  Researchers can also genetically modify these bacteria to produce a specific protein like anti-tumor cytotoxins for cancer treatment. [ 4 ]


Yet, this is not to say that they don't come with their own set of challenges and limitations. For one, the genetic modifications of the bacteria used can be manipulated by recent or unforeseen mutations, leading to a decrease in the efficacy of the drug and drug carrier. [ 4 ]  Moreover, the therapeutic proteins produced may have incomplete protein folding, decreasing the drug's effectiveness or causing unforeseen side effects. [ 4 ]  Generally speaking, using bacteria may provide some advantages, but further research and development are still needed to address their limitations.


Another example of bio-hybrid drug carriers is human cells, like macrophages, which offer compatibility with the human immune system and a simple way to load drugs as a bio-hybrid drug carrier. [ 4 ]  Leukocytes demonstrate great promise because Tumor cells secrete large amounts of chemoattractants when the cell undergoes inflammation. [ 4 ]  This secretion of chemoattractants naturally attracts leukocytes, such as macrophages, to the T cell location. [ 4 ]  Thus, with their well-known chemotactic homing behavior to inflammation or pathogens' sites in mind, researchers can manipulate leukocytes to carry and deliver a therapeutic payload to the tumor site. However, this is not to say that Biological and bio-hybrid drug carriers do not have challenges and limitations of their own. For example, Leukocytes cannot penetrate deeply into the tumors, have a low capacity for carrying drugs, and slow down when the tumor size reduces. Thus, similar to bacteria drug carriers, further research and development are still needed to address their limitations and improve the overall drug delivery system.


The applications of chemotactic drug delivery systems include but are not limited to  cancer  therapy, wound healing, and inflammation. The ability to target specific cells and locations within the body through chemical cues has opened up new avenues for the field of drug delivery, allowing for increased drug efficacy and reducing harmful side effects.


Cancer is not just one disease but a group of diseases involving abnormal cell growth and metastasis of such cells to other body parts. [ 20 ] [ 21 ]  There are also several types of cancers, each with its own distinctive characteristics and stages that may require different treatment or targeted drug delivery approaches. [ 21 ] [ 22 ]  Yet, even these treatments have their own advantages and disadvantages. Thus, since the discovery of cancer, researchers have constantly been developing new and innovative cancer treatments, including chemotactic drug delivery. For example, and as mentioned earlier in this article, researchers have sought to use microdroplets, protocells, and biological and bio-hybrid drug carriers to deliver drugs to cancer cells in a more effective manner, while reducing unwanted side effects. [ 2 ] [ 4 ] [ 12 ] [ 15 ] [ 19 ]  In fact, the justification for using such systems, guided by chemotaxis, is that the environment inside a tumor has a higher resting temperature, higher peroxide concentration, lower pH, and a lower oxygen concentration than its surrounding tissue. [ 4 ]  With these unique conditions, researchers can exploit chemotactic drug delivery to target tumor cells directly, avoiding healthy tissues, reducing toxicity, improving drug efficacy, and decreasing drug dosage. [ 12 ] [ 13 ]


Inflammation  is the body's response to foreign objects, irritants, germs, and even pathogens. Although such a response is standard in some cases, if left untreated, chronic inflammation can lead to muscle degeneration, gastrointestinal disorders, and some types of cancers. [ 23 ] [ 24 ]  While most treatments, such as anti-inflammatory drugs and steroid injections, can help relieve symptoms, they often fail to address the condition's underlying cause. Therefore, researchers have sought to explore new and innovative ways of inflammation treatment, such as chemotactic drug delivery.


One promising drug delivery system was based on engineered neutrophils that targeted inflammation sites through chemotaxis's unique properties. [ 4 ] [ 7 ]  This approach took advantage of the concentration difference between iNOS and ROS for inflammatory disease sites and normal tissues. [ 7 ]  By doing so, this drug delivery system provides the possibility to target areas of inflammation, increase drug efficacy, and minimize damage to the surrounding tissue. [ 3 ] [ 11 ]  Moreover, because this concentration gradient is ubiquitous in the microenvironment of inflammatory diseases, common drug-targeting limitations such as individual differences can be avoided. [ 7 ]  Another example of an innovative drug delivery system that uses the property of chemotaxis is leukocytes. [ 4 ]  Indeed, during inflammation, the molecules on a cell that allows for adhesion are overly produced. [ 4 ]  With this unique condition, researchers can modify leukocytes to quickly detect the cell, attach itself to the surface, and deliver a therapeutic payload. [ 4 ]  Overall, many promising therapies and drug delivery systems are being developed to target inflammation more effectively. Chemotactic drug delivery systems are just one of many promising avenues that seek to increase target sites specifically, decreasing the needed drug dosage, reducing toxicity, and increasing drug efficacy. [ 3 ] [ 4 ] [ 11 ]


While this emerging field of drug delivery shows excellent promise in targeting specific cells and locations within the body, understanding current challenges and drawbacks can allow researchers to optimize design, development, and delivery to improve the overall outcome of their medical treatment.


Generally speaking, chemotactic drug-targeting is a drug delivery strategy with promising avenues for treating diseases such as cancer and inflammation. This approach mimics the biological process of chemotaxis, which biological organisms use to detect, maneuver, and react to chemical signals in their environment. By applying this technique to targeted drug delivery, researchers aim to create drugs that can precisely reach their intended targets, minimizing the potential for side effects, improving drug efficacy, and decreasing drug dosage. Some examples include but are not limited to microdroplets, protocells, biological and bio-hybrid drug carriers, leukocytes, and neutrophils.