Bioavailability
Encyclopedia
In pharmacology
, bioavailability (BA) is a subcategory of absorption and is used to describe the fraction of an administered dose
of unchanged drug that reaches the systemic circulation
, one of the principal pharmacokinetic
properties of drugs
. By definition, when a medication is administered intravenously, its bioavailability is 100%. However, when a medication is administered via other routes
(such as orally), its bioavailability generally decreases (due to incomplete absorption and first-pass metabolism) or may vary from patient to patient. Bioavailability is one of the essential tools in pharmacokinetics, as bioavailability must be considered when calculating dosages for non-intravenous routes of administration.
For dietary supplements, herbs and other nutrients in which the route of administration is nearly always oral, bioavailability generally designates simply the quantity or fraction of the ingested dose that is absorbed.
Bioavailability is defined slightly differently for drugs as opposed to dietary supplements primarily due to the method of administration and Food and Drug Administration
regulations.
Bioaccessibility is a concept related to bioavailability in the context of biodegradation
and environmental pollution. A molecule
(often a persistent organic pollutant
) is said to be bioavailable when "[it] is available to cross an organism’s cellular membrane from the environment, if the organism has access to the chemical."
It is denoted by the letter f (or, if expressed in percent, by F).
In both pharmacology and nutrition sciences, bioavailability is measured by calculating the area under curve (AUC) of the drug concentration time profile.
(i.e., after oral, rectal, transdermal
, subcutaneous, or sublingual
administration), with the bioavailability of the same drug following intravenous administration. It is the fraction of the drug absorbed through non-intravenous administration compared with the corresponding intravenous administration of the same drug. The comparison must be dose normalized (e.g. account for different doses or varying weights of the subjects); consequently, the amount absorbed is corrected by dividing the corresponding dose administered.
In pharmacology, in order to determine absolute bioavailability of a drug, a pharmacokinetic study must be done to obtain a plasma drug concentration vs time plot for the drug after both intravenous (iv) and extravascular (non-intravenous, i.e., oral) administration. The absolute bioavailability is the dose-corrected area under curve (AUC) non-intravenous divided by AUC intravenous. For example, the formula for calculating F for a drug administered by the oral route (po) is given below.
Therefore, a drug given by the intravenous route will have an absolute bioavailability of 100% (f=1), whereas drugs given by other routes usually have an absolute bioavailability of less than one.
If we compare the two different dosage forms having same active ingredients and compare the two drug bioavailability is called comparative bioavailability.
Although knowing the true extent of systemic absorption (referred to as absolute bioavailability) is clearly useful, in practice it is not determined as frequently as one may think. The reason for this is that its assessment requires an intravenous reference, that is, a route of administration that guarantees that all of the administered drug reaches the systemic circulation. Such studies come at considerable cost, not least of which is the necessity to conduct preclinical toxicity tests to ensure adequate safety, as well as there being potential problems due to solubility limitations. These limitations may be overcome, however, by administering a very low dose (typically a few micrograms) of an isotopically labelled drug concomitantly with a therapeutic non-labelled oral dose. Providing the isotopically-labelled intravenous dose is sufficiently low so as not to perturb the systemic drug concentrations achieved from the absorbed oral dose, then the intravenous and oral pharmacokinetics can be deconvoluted by virtue of the their different isotopic constitution and thereby determine the oral and intravenous pharmacokinetics from the same dose administration. This technique eliminates pharmacokinetic issues on non-equivalent clearance as well as enabling the intravenous dose to be administered with a minimum of toxicology and formulation. The technique was first applied using stable-isotopes such as C-13 and mass-spectrometry to distinguish the isotopes by mass difference. More recently, C-14 labelled drugs are administered intravenously and accelerator mass spectrometry (AMS) used to measure the isotopically labelled drug along with mass spectrometry for the unlabelled drug.
There is no regulatory requirement to define the intravenous pharmacokinetics or absolute bioavailability however regulatory authorities do sometimes ask for absolute bioavailbility information of the extravascular route in cases in which the bioavailability is apparently low or variable and there is a proven relationship between the pharmacodynamics
and the pharmacokinetics at therapeutic doses. In all such cases, to conduct an absolute bioavailability study requires that the drug be given intravenously.
Intravenous administration of a developmental drug can provide valuable information on the fundamental pharmacokinetic parameters of volume of distribution
(V) and clearance
(CL).
Relative bioavailability is one of the measures used to assess bioequivalence
(BE) between two drug products. For FDA approval, a generic manufacturer must demonstrate that the 90% confidence interval
for the ratio of the mean responses (usually of AUC and the maximum concentration, Cmax) of its product to that of the "Brand Name drug" is within the limits of 80% to 125%. While AUC refers to the extent of bioavailability, Cmax refers to the rate of bioavailability. When Tmax is given, it refers to the time it takes for a drug to reach Cmax.
While the mechanisms by which a formulation affects bioavailability and bioequivalence have been extensively studied in drugs, formulation factors that influence bioavailability and bioequivalence in nutritional supplements are largely unknown. As a result, in nutritional sciences, relative bioavailability or bioequivalence is the most common measure of bioavailability, comparing the bioavailability of one formulation of the same dietary ingredient to another.
Other factors may include, but are not limited to:
Each of these factors may vary from patient to patient (inter-individual variation), and indeed in the same patient over time (intra-individual variation). In clinical trial
s, inter-individual variation is a critical measurement used to assess the bioavailability differences from patient to patient in order to ensure predictable dosing.
; and dosing intervals of nutritional supplements, therefore, are not critical in contrast to drug therapy.
In addition, the lack of defined methodology and regulations surrounding the consumption of dietary supplements hinders the application of bioavailability measures in comparison to drugs. In clinical trials with dietary supplements, bioavailability primarily focuses on statistical descriptions of mean or average AUC differences between treatment groups, while often failing to compare or discuss their standard deviations or inter-individual variation. This failure leaves open the question of whether or not an individual in a group is likely to experience the benefits described by the mean-difference comparisons. Further, even if this issue were discussed, it would be difficult to communicate meaning of these inter-subject variances to consumers and/or their physicians.
Pharmacology
Pharmacology is the branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function...
, bioavailability (BA) is a subcategory of absorption and is used to describe the fraction of an administered dose
Dose (biochemistry)
A dose is a quantity of something that may impact an organism biologically; the greater the quantity, the larger the dose. In nutrition, the term is usually applied to how much of a specific nutrient is in a person's diet or in a particular food, meal, or dietary supplement...
of unchanged drug that reaches the systemic circulation
Systemic circulation
Systemic circulation is the part of the cardiovascular system which carries oxygenated blood away from the heart to the body, and returns deoxygenated blood back to the heart. This physiologic theory of circulation was first described by William Harvey...
, one of the principal pharmacokinetic
Pharmacokinetics
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...
properties of drugs
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
. By definition, when a medication is administered intravenously, its bioavailability is 100%. However, when a medication is administered via other routes
Route of administration
A route of administration in pharmacology and toxicology is the path by which a drug, fluid, poison, or other substance is taken into the body.-Classification:Routes of administration are usually classified by application location...
(such as orally), its bioavailability generally decreases (due to incomplete absorption and first-pass metabolism) or may vary from patient to patient. Bioavailability is one of the essential tools in pharmacokinetics, as bioavailability must be considered when calculating dosages for non-intravenous routes of administration.
For dietary supplements, herbs and other nutrients in which the route of administration is nearly always oral, bioavailability generally designates simply the quantity or fraction of the ingested dose that is absorbed.
Bioavailability is defined slightly differently for drugs as opposed to dietary supplements primarily due to the method of administration and Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
regulations.
Bioaccessibility is a concept related to bioavailability in the context of biodegradation
Biodegradation
Biodegradation or biotic degradation or biotic decomposition is the chemical dissolution of materials by bacteria or other biological means...
and environmental pollution. A molecule
Molecule
A molecule is an electrically neutral group of at least two atoms held together by covalent chemical bonds. Molecules are distinguished from ions by their electrical charge...
(often a persistent organic pollutant
Persistent organic pollutant
thumb|right|275px|State parties to the Stockholm Convention on Persistent Organic PollutantsPersistent organic pollutants are organic compounds that are resistant to environmental degradation through chemical, biological, and photolytic processes...
) is said to be bioavailable when "[it] is available to cross an organism’s cellular membrane from the environment, if the organism has access to the chemical."
In pharmacology
In pharmacology, bioavailability is a measurement of the extent to which a drug reaches the systemic circulation.It is denoted by the letter f (or, if expressed in percent, by F).
In nutritional sciences
In nutritional sciences, which covers the intake of nutrients and non-drug dietary ingredients, the concept of bioavailability lacks the well-defined standards associated with the pharmaceutical industry. The pharmacological definition cannot apply to these substances because utilization and absorption is a function of the nutritional status and physiological state of the subject, resulting in even greater differences from individual to individual (inter-individual variation). Therefore, bioavailability for dietary supplements can be defined as the proportion of the substance capable of being absorbed and available for use or storage.In both pharmacology and nutrition sciences, bioavailability is measured by calculating the area under curve (AUC) of the drug concentration time profile.
In environmental sciences
Bioavailability is commonly a limiting factor in the production of crops (due to solubility limitation or adsorption of plant nutrients to soil colloids) and in the removal of toxic substances from the food chain by microorganisms (due to sorption to or partitioning of otherwise degradable substances into inaccessible phases in the environment). A noteworthy example for agriculture is plant phosphorus deficiency induced by precipitation with iron and aluminum phosphates at low soil pH and precipitation with calcium phosphates at high soil pH. Toxic materials in soil, such as lead from sloughed paint may be rendered unavailable to animals ingesting contaminated soil by supplying phosphorus fertilizers in excess. Organic pollutants such as solvents or pesticides may be rendered unavailable to microorganisms and thus persist in the environment when they are adsorbed to soil minerals or partition into hydrophobic organic matter.Absolute bioavailability
Absolute bioavailability compares the bioavailability of the active drug in systemic circulation following non-intravenous administrationRoute of administration
A route of administration in pharmacology and toxicology is the path by which a drug, fluid, poison, or other substance is taken into the body.-Classification:Routes of administration are usually classified by application location...
(i.e., after oral, rectal, transdermal
Transdermal
Transdermal is a route of administration wherein active ingredients are delivered across the skin for systemic distribution. Examples include transdermal patches used for medicine delivery, and transdermal implants used for medical or aesthetic purposes....
, subcutaneous, or sublingual
Sublingual
Sublingual, literally 'under the tongue', from Latin, refers to the pharmacological route of administration by which drugs diffuse into the blood through tissues under the tongue...
administration), with the bioavailability of the same drug following intravenous administration. It is the fraction of the drug absorbed through non-intravenous administration compared with the corresponding intravenous administration of the same drug. The comparison must be dose normalized (e.g. account for different doses or varying weights of the subjects); consequently, the amount absorbed is corrected by dividing the corresponding dose administered.
In pharmacology, in order to determine absolute bioavailability of a drug, a pharmacokinetic study must be done to obtain a plasma drug concentration vs time plot for the drug after both intravenous (iv) and extravascular (non-intravenous, i.e., oral) administration. The absolute bioavailability is the dose-corrected area under curve (AUC) non-intravenous divided by AUC intravenous. For example, the formula for calculating F for a drug administered by the oral route (po) is given below.
Therefore, a drug given by the intravenous route will have an absolute bioavailability of 100% (f=1), whereas drugs given by other routes usually have an absolute bioavailability of less than one.
If we compare the two different dosage forms having same active ingredients and compare the two drug bioavailability is called comparative bioavailability.
Although knowing the true extent of systemic absorption (referred to as absolute bioavailability) is clearly useful, in practice it is not determined as frequently as one may think. The reason for this is that its assessment requires an intravenous reference, that is, a route of administration that guarantees that all of the administered drug reaches the systemic circulation. Such studies come at considerable cost, not least of which is the necessity to conduct preclinical toxicity tests to ensure adequate safety, as well as there being potential problems due to solubility limitations. These limitations may be overcome, however, by administering a very low dose (typically a few micrograms) of an isotopically labelled drug concomitantly with a therapeutic non-labelled oral dose. Providing the isotopically-labelled intravenous dose is sufficiently low so as not to perturb the systemic drug concentrations achieved from the absorbed oral dose, then the intravenous and oral pharmacokinetics can be deconvoluted by virtue of the their different isotopic constitution and thereby determine the oral and intravenous pharmacokinetics from the same dose administration. This technique eliminates pharmacokinetic issues on non-equivalent clearance as well as enabling the intravenous dose to be administered with a minimum of toxicology and formulation. The technique was first applied using stable-isotopes such as C-13 and mass-spectrometry to distinguish the isotopes by mass difference. More recently, C-14 labelled drugs are administered intravenously and accelerator mass spectrometry (AMS) used to measure the isotopically labelled drug along with mass spectrometry for the unlabelled drug.
There is no regulatory requirement to define the intravenous pharmacokinetics or absolute bioavailability however regulatory authorities do sometimes ask for absolute bioavailbility information of the extravascular route in cases in which the bioavailability is apparently low or variable and there is a proven relationship between the pharmacodynamics
Pharmacodynamics
Pharmacodynamics is the study of the biochemical and physiological effects of drugs on the body or on microorganisms or parasites within or on the body and the mechanisms of drug action and the relationship between drug concentration and effect...
and the pharmacokinetics at therapeutic doses. In all such cases, to conduct an absolute bioavailability study requires that the drug be given intravenously.
Intravenous administration of a developmental drug can provide valuable information on the fundamental pharmacokinetic parameters of volume of distribution
Volume of distribution
The volume of distribution , also known as apparent volume of distribution, is a pharmacological term used to quantify the distribution of a medication between plasma and the rest of the body after oral or parenteral dosing...
(V) and clearance
Clearance (medicine)
In medicine, the clearance is a measurement of the renal excretion ability. Although clearance may also involve other organs than the kidney, it is almost synonymous with renal clearance or renal plasma clearance. Each substance has a specific clearance that depends on its filtration characteristics...
(CL).
Relative bioavailability and bioequivalence
In pharmacology, relative bioavailability measures the bioavailability (estimated as the AUC) of a formulation (A) of a certain drug when compared with another formulation (B) of the same drug, usually an established standard, or through administration via a different route. When the standard consists of intravenously administered drug, this is known as absolute bioavailability (see above).
Relative bioavailability is one of the measures used to assess bioequivalence
Bioequivalence
Bioequivalence is a term in pharmacokinetics used to assess the expected in vivo biological equivalence of two proprietary preparations of a drug...
(BE) between two drug products. For FDA approval, a generic manufacturer must demonstrate that the 90% confidence interval
Confidence interval
In statistics, a confidence interval is a particular kind of interval estimate of a population parameter and is used to indicate the reliability of an estimate. It is an observed interval , in principle different from sample to sample, that frequently includes the parameter of interest, if the...
for the ratio of the mean responses (usually of AUC and the maximum concentration, Cmax) of its product to that of the "Brand Name drug" is within the limits of 80% to 125%. While AUC refers to the extent of bioavailability, Cmax refers to the rate of bioavailability. When Tmax is given, it refers to the time it takes for a drug to reach Cmax.
While the mechanisms by which a formulation affects bioavailability and bioequivalence have been extensively studied in drugs, formulation factors that influence bioavailability and bioequivalence in nutritional supplements are largely unknown. As a result, in nutritional sciences, relative bioavailability or bioequivalence is the most common measure of bioavailability, comparing the bioavailability of one formulation of the same dietary ingredient to another.
Factors influencing bioavailability
The absolute bioavailability of a drug, when administered by an extravascular route, is usually less than one (i.e., F <100%). Various physiological factors reduce the availability of drugs prior to their entry into the systemic circulation. Whether a drug is taken with or without food will also affect absorption, other drugs taken concurrently may alter absorption and first-pass metabolism, intestinal motility alters the dissolution of the drug and may affect the degree of chemical degradation of the drug by intestinal microflora. Disease states affecting liver metabolism or gastrointestinal function will also have an effect.Other factors may include, but are not limited to:
- Physical properties of the drug (hydrophobicityHydrophobeIn chemistry, hydrophobicity is the physical property of a molecule that is repelled from a mass of water....
, pKaAcid dissociation constantAn acid dissociation constant, Ka, is a quantitative measure of the strength of an acid in solution. It is the equilibrium constant for a chemical reaction known as dissociation in the context of acid-base reactions...
, solubilitySolubilitySolubility is the property of a solid, liquid, or gaseous chemical substance called solute to dissolve in a solid, liquid, or gaseous solvent to form a homogeneous solution of the solute in the solvent. The solubility of a substance fundamentally depends on the used solvent as well as on...
) - The drug formulation (immediate release, excipients used, manufacturing methods, modified release – delayed release, extended release, sustained release, etc.)
- Whether the formulation is administered in a fed or fastedFastingFasting is primarily the act of willingly abstaining from some or all food, drink, or both, for a period of time. An absolute fast is normally defined as abstinence from all food and liquid for a defined period, usually a single day , or several days. Other fasts may be only partially restrictive,...
state - Gastric emptying rate
- Circadian differences
- Interactions with other drugs/foods:
- Interactions with other drugs (e.g., antacidAntacidAn antacid is a substance which neutralizes stomach acidity.-Mechanism of action:Antacids perform a neutralization reaction, increasing the pH to reduce acidity in the stomach. When gastric hydrochloric acid reaches the nerves in the gastrointestinal mucosa, they signal pain to the central nervous...
s, alcohol, nicotine) - Interactions with other foods (e.g., grapefruit juiceGrapefruit juiceGrapefruit juice is the fruit juice from grapefruits. It is rich in Vitamin C and ranges from sweet-tart to very sour. It is considered by some cultures to be a mystical tonic which promotes health and vigor. Certain civilizations have had holy men who live on Grapefruit juice alone...
, pomello, cranberry juiceCranberry juiceCranberry juice is the juice of the cranberry. Commercially, it is sold in either as a pure juice, which is quite tart, or, more commonly, as cranberry juice "cocktail" or "drink" , in blends with other juices, such as apple or grape, or mixed with water and corn syrup, sugar, or an artificial...
, brassicaBrassicaBrassica is a genus of plants in the mustard family . The members of the genus may be collectively known either as cabbages, or as mustards...
vegetables)
- Interactions with other drugs (e.g., antacid
- Transporters: Substrate of efflux transporters (e.g. P-glycoproteinP-glycoproteinP-glycoprotein 1 also known as multidrug resistance protein 1 or ATP-binding cassette sub-family B member 1 or cluster of differentiation 243 is a glycoprotein that in humans is encoded by the ABCB1 gene...
) - Health of the GI tract
- EnzymeEnzymeEnzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
induction/inhibition by other drugs/foods:- Enzyme induction (increased rate of metabolism), e.g., PhenytoinPhenytoinPhenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...
induces CYP1A2CYP1A2Cytochrome P450 1A2 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body...
, CYP2C9CYP2C9Cytochrome P450 2C9 is a protein that in humans is encoded by the CYP2C9 gene.- Function :CYP2C9 is an important cytochrome P450 enzyme with a major role in the oxidation of both xenobiotic and endogenous compounds. CYP2C9 makes up about 18% of the cytochrome P450 protein in liver microsomes...
, CYP2C19CYP2C19Cytochrome P450 2C19 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body. It is involved in the metabolism of several...
, and CYP3A4CYP3A4Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in... - Enzyme inhibitionEnzyme inhibitorAn enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
(decreased rate of metabolism), e.g., grapefruit juice inhibits CYP3A → higher nifedipine concentrations
- Enzyme induction (increased rate of metabolism), e.g., Phenytoin
- Individual variation in metabolic differences
- Age: In general, drugs are metabolized more slowly in fetal, neonatal, and geriatric populations
- Phenotypic differences, enterohepatic circulationEnterohepatic circulationEnterohepatic circulation refers to the circulation of biliary acids from the liver, where they are produced and secreted in the bile, to the small intestine, where it aids in digestion of fats and other substances, back to the liver....
, diet, gender
- Disease state
- E.g., hepatic insufficiency, poor renal function
Each of these factors may vary from patient to patient (inter-individual variation), and indeed in the same patient over time (intra-individual variation). In clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s, inter-individual variation is a critical measurement used to assess the bioavailability differences from patient to patient in order to ensure predictable dosing.
Bioavailability of drugs versus dietary supplements
In comparison to drugs, there are significant differences in dietary supplements that impact the evaluation of their bioavailability. These differences include the following: the fact that nutritional supplements provide benefits that are variable and often qualitative in nature; the measurement of nutrient absorption lacks the precision; nutritional supplements are consumed for prevention and well-being; nutritional supplements do not exhibit characteristic dose-response curvesDose-response relationship
The dose-response relationship, or exposure-response relationship, describes the change in effect on an organism caused by differing levels of exposure to a stressor after a certain exposure time...
; and dosing intervals of nutritional supplements, therefore, are not critical in contrast to drug therapy.
In addition, the lack of defined methodology and regulations surrounding the consumption of dietary supplements hinders the application of bioavailability measures in comparison to drugs. In clinical trials with dietary supplements, bioavailability primarily focuses on statistical descriptions of mean or average AUC differences between treatment groups, while often failing to compare or discuss their standard deviations or inter-individual variation. This failure leaves open the question of whether or not an individual in a group is likely to experience the benefits described by the mean-difference comparisons. Further, even if this issue were discussed, it would be difficult to communicate meaning of these inter-subject variances to consumers and/or their physicians.
Nutritional science: reliable and universal bioavailability
One way to resolve this problem is to define "reliable bioavailability" as positive bioavailability results (an absorption meeting a predefined criteria) that include 84% of the trial subjects and "universal bioavailability" as those that include 98% of the trial subjects. This reliable-universal framework would improve communications with physicians and consumers such that, if it were included on products labels for example, make educated choices as to the benefits of a formulation for them directly. In addition, the reliable-universal framework is similar to the construction of confidence intervals, which statisticians have long offered as one potential solution for dealing with small samples, violations of statistical assumptions or large standard deviations.See also
- ADME-Tox
- Lipinski's Rule of 5
- Biopharmaceutics Classification SystemBiopharmaceutics Classification SystemThe Biopharmaceutics Classification System is a guide for predicting the intestinal drug absorption provided by the U.S. Food and Drug Administration . The fundamental basis for the BCS was established by Dr...
- Caco-2Caco-2The Caco-2 cell line is a continuous line of heterogeneous human epithelial colorectal adenocarcinoma cells, developed by the Sloan-Kettering Institute for Cancer Research through research conducted by Dr...