Bioavailability, definition

According to the bioavailability definition given above and because of the (most frequently) linear relationship between AUC and the fraction, F, of dose reaching the systemic circulation, AUC is used as a measure of the amount of drug reaching the general circulation. 

The term bioavailability has various definitions. Previously, the authors of this chapter have defined bioavailability as the proportion of a nutrient (or other food component) that is digested, absorbed and utilised in normal metabolism - with the practical measurement of bioavailability usually relying upon estimates of amounts absorbed (Southon and Faulks, 2001). Biological activity, or bioactivity , has been viewed and described as a separate stage which follows on from bioavailability in the journey of a compound from food to function. However, here we present a new definition of bioavailability that recognises the functional consequences of absorption. 

The AUC is a measure of bioavailability, i.e. the amount of substance in the central compartment that is available to the organism. It takes a maximal value under intravenous administration, and is usually less after oral administration or parenteral injection (such as under the skin or in muscle). In the latter cases, losses occur in the gut and at the injection sites. The definition also shows that for a constant dose D, the area under the curve varies inversely with the rate of elimination kp and with the volume of distribution V. Figure 39.6 illustrates schematically the different cases that can be obtained by varying the volume of distribution Vp and the rate of elimination k both on linear and semilogarithmic diagrams. These diagrams show that the slope (time course) of the curves are governed by the rate of elimination and that elevation (amplitude) of the curve is determined by the volume of distribution. 

Whenever a drug is administered by an extra-vascular route, there is a danger that part of the dose may not reach the blood (i.e., absorption may not be complete). When the intravenous route is used, the drug is placed directly in the blood therefore an IV injection is, by definition, 100% absorbed. The absolute bioavailability of an extravascular dosage form is defined relative to an IV injection. If IV data are not available, the relative bioavailability may be defined relative to a standard dosage form. For example, the bioavailability of a tablet may be defined relative to an oral solution of the drug. 

Bioavailability depends not only on having the drug in solution, but also on the drug s permeability. A jejunal permeability of at least 2-4 x 10 4cm/s, measured in human subjects by intubation, is considered high [97]. For many drugs and other substances, this permeability corresponds to a fraction absorbed of 90% or better. Amidon et al. [97] thus proposed a Biopharmaceutics Classification System (BCS) for drugs based on the above definitions of these two parameters. Table 3 defines the BCS and includes some drugs representative of each class. 

Another refinement, that avoids the necessity of developing suitable fecal extraction and chromatographic methods, is to dose the radiolabeled compound by both the i.v. and p.o. routes in two separate studies. Knowing that, by definition, the whole of the i.v. dose must have been bioavailable, a comparison of the proportion of the dose in the urine after the two different routes allows estimation of the percent absorbed. An analogous approach can be used without the use of a radiolabel, when the urine from the two studies is analyzed either for the parent compound or, more usually, for a major common metabolite. Assuming quantitatively identical clearance after both the i.v. and p.o. doses, the ratio of the amounts of analyte in the two experiments gives the absorption. 

Pharmacokinetic Definition of Intestinal Absorption (fa), Presystemic Metabolism (Ec and Eh) and Absolute Bioavailability (F) of Drugs Administered Orally to Humans... 

Definition of Absorption and Bioavailability of Drugs following Oral Administration... 

The general definition of the bioavailability (F) of a drug following oral administration is the rate at, and extent to which, a pharmacologically active drug reaches the systemic circulation. The bioavaiiabiiity (F) of a compound is a consequence of several processes shown in Eq. (1) ... 

The term bioavailability has different meanings in different contexts and disciplines. Numerous definitions of bioavailability exist. Research on the relationship between bioavailability and chemical speciation (forms) originated in the field of soil fertility in the search for a good predictor for the bioavailability of essential plant nutrients (Traina and Laperche 1999). It is well accepted that dissolved nutrients are more labile and bioavailable to plants than solid-phase forms (including sorbed species). The same has been considered to be true for organic contaminants and their availability for microbial degradation. 

Bioavailability issues have been reviewed previously (Mihelcic etal. 1993 Boesten 1993 Baveye and Bladon 1999 Ehlers and Luthy 2003). In this review, we discuss specifically the bioavailability of soil- or sediment-sorbed organic contaminants to pollutant-degrading bacteria. Direct uptake of sorbed contaminants is perhaps the most controversial and least understood process. The definition of bioavailability given by Alexander (2000) will be used in this review. The term bioaccessibility encompasses what is immediately available plus that which may become available, whereas bioavailability refers to what is available immediately. 

Wheat bran has been the fiber source most commonly used to study effects of dietary fiber on calcium absorption in controlled laboratory studies. However, wheat bran and other forms of fiber as they occur in food products present several disadvantages in terms of definition and by concurrently altering intakes of other substances or materials known or suspected of having an adverse effect on the bioavailability of calcium such as phytates and oxalates (5,13,17,22-28). Several studies have been conducted which have sought to separate or compare the effects of phytate and fiber... 

Phase I studies evaluate the pharmacokinetics and safety of the drug in a small number (tens) of healthy volunteers. Phase I studies are sometimes conducted in a small patient population (Proof of Concept studies) with a specific objective such as the validation of the relevance of preclinical models in man. The purpose of these studies may be the rapid elimination of potential failures from the pipeline, definition of biological markers for efficacy or toxicity, or demonstration of early evidence of efficacy. These studies have a potential go/no-go decision criteria such as safety, tolerability, bioavailability/PK, pharmacodynamics, and efficacy. Dosage forms used in Phase I or Proof of Concept studies must be developed with the objectives of the clinical study in mind. 

Oral bioavailability is one of principal pharmacokinetic properties in drug discovery. It represents the percentage of an oral dose that is available to produce pharmacological actions, in other words, the fraction of the oral dose that reaches the system circulation in an active form. By the definition, when a drug is administered intravenously, its bioavailability is 100%. However, when a medication is administered via other routes, especially orally, its bioavailability decreases due to incomplete absorption and first-pass metabolism. 

Balant, L. (1991). Is there a need for more precise definitions of bioavailability Eur. ]. Clin. Pharmacol. 40,123-126. 

The intravenous curve is, by definition, a representation of 100% bioavailability as the drug was put in its entirety into the vein. The oral curve has an area under it approximately 75% the size of the intravenous curve, and this suggests that 25% of the oral dose failed to get into the circulation. The oral bioavailability of the drug is the proportion getting into the vascular compartment, and can be measured if there is an intravenous dose curve available for the same subject at the same dose. In this example, F (the fraction bioavailable) is 0.75. It might be as high as 1.0 (100%) for some steroids, or as low as 0.1 (10%) or even less for poorly absorbed aminoglycosides. 

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