Inpharmacology,bioavailability is a subcategory ofabsorption and is the fraction (%) of an administereddrug that reaches thesystemic circulation.[1]
By definition, when a medication is administeredintravenously, its bioavailability is 100%.[2][3] However, when a medication is administered viaroutes other than intravenous, its bioavailability is lower due to intestinal epithelium absorption andfirst-pass metabolism. Thereby, mathematically, bioavailability equals the ratio of comparing thearea under the plasma drug concentration curve versus time (AUC) for the extravascular formulation to the AUC for the intravascular formulation.[4] AUC is used because AUC is proportional to the dose that has entered the systemic circulation.[5]
Bioavailability of a drug is anaverage value; to takepopulation variability into account,deviation range is shown as±.[4] To ensure that the drug taker who has poor absorption is dosed appropriately, the bottom value of the deviation range is employed to represent real bioavailability and to calculate the drug dose needed for the drug taker to achieve systemic concentrations similar to the intravenous formulation.[4] To dose without knowing the drug taker's absorption rate, the bottom value of the deviation range is used in order to ensure the intended efficacy, unless the drug is associated with a narrowtherapeutic window.[4]
Fordietary 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.[6][7][8]
Bioavailability is a term used to describe the percentage of an administered dose of a xenobiotic that reaches the systemic circulation.[9]It is denoted by the letterf (or, if expressed in percent, byF).
Innutritional science, 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,[10] 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 administered substance capable of being absorbed and available for use or storage.[11]
In bothpharmacology and nutrition sciences, bioavailability is measured by calculating thearea under curve (AUC) of the drug concentration time profile.
Bioavailability is the measure by which various substances in the environment may enter into living organisms. It is commonly a limiting factor in the production of crops (due to solubility limitation or absorption 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 lowsoil pH and precipitation with calcium phosphates at high soil pH.[12] Toxic materials in soil, such as lead from paint may be rendered unavailable to animals ingesting contaminated soil by supplying phosphorus fertilizers in excess.[13] Organic pollutants such as solvents or pesticides[14] may be rendered unavailable to microorganisms and thus persist in the environment when they are adsorbed to soil minerals[15] or partition into hydrophobic organic matter.[16]
Absolute bioavailability compares the bioavailability of the active drug in systemic circulation following non-intravenousadministration (i.e., afteroral, buccal, ocular, nasal, rectal,transdermal,subcutaneous, orsublingual administration), with the bioavailability of the same drug following intravenous administration. It is the fraction of exposure to a drug (AUC) through non-intravenous administration compared with the corresponding intravenous administration of the same drug.[17] 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, apharmacokinetic study must be done to obtain aplasma 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 byAUC intravenous. The formula for calculating the absolute bioavailability,F, of a drug administered orally (po) is given below (whereD is dose administered).
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 ofless than one.If we compare the two different dosage forms having same active ingredients and compare the two drug bioavailability is called comparative bioavailability.[18]
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 anintravenous reference; that is, a route of administration that guarantees all of the administered drug reaches 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 potential problems due to solubility limitations. These limitations may be overcome, however, by administering a very low dose (typically a few micrograms) of anisotopically labelled drug concomitantly with a therapeutic non-isotopically labelled oral dose (the isotopically labelled intravenous dose is sufficiently low so as not to perturb the systemic drug concentrations achieved from the non-labelled oral dose). The intravenous and oral concentrations can then be deconvoluted by virtue of their different isotopic constitution, and can thus be used to determine the oral and intravenous pharmacokinetics from the same dose administration. This technique eliminates pharmacokinetic issues with 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 as13C and mass-spectrometry to distinguish the isotopes by mass difference. More recently,14C 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.[19]
There is no regulatory requirement to define the intravenous pharmacokinetics or absolute bioavailability however regulatory authorities do sometimes ask for absolute bioavailability information of the extravascular route in cases in which the bioavailability is apparently low or variable and there is a proven relationship between thepharmacodynamics and the pharmacokinetics at therapeutic doses. In all such cases, to conduct an absolute bioavailability study requires that the drug be given intravenously.[20]
Intravenous administration of a developmental drug can provide valuable information on the fundamental pharmacokinetic parameters ofvolume of distribution (V) andclearance (CL).[20]
In pharmacology, relative bioavailability measures the bioavailability (estimated as theAUC) 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 (seeabove).
Relative bioavailability is one of the measures used to assessbioequivalence (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 ofAUC and the maximum concentration,Cmax) of its product to that of the "brand name drug"[OB] is within the limits of 80% to 125%. WhereAUC refers to the concentration of the drug in the blood over timet = 0 tot = ∞,Cmax refers to the maximum concentration of the drug in the blood. WhenTmax is given, it refers to the time it takes for a drug to reachCmax.
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.[21] 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.
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:
Each of these factors may vary from patient to patient (inter-individual variation), and indeed in the same patient over time (intra-individual variation). Inclinical trials, inter-individual variation is a critical measurement used to assess the bioavailability differences from patient to patient in order to ensure predictable dosing.
^ TH: One of the few exceptions where a drug showsF of over 100% istheophylline. If administered as an oral solutionF is 111%, since the drug is completely absorbed and first-pass metabolism in the lung after intravenous administration is bypassed.[22]
^ OB: Reference listed drug products (i.e., innovator's) as well asgeneric drug products that have been approved based on anAbbreviated New Drug Application are given in FDA'sOrange Book.
Bioavailability is the major factor affecting dietary requirements (Sandstrom, 1997). Flesh foods facilitate bioavailability, although indigestible Zn-binding ligands decrease bioavailability (Mills, 1985).
Bioavailability strictly refers to both the uptake and metabolic utilization of a nutrient.
