Absorption bioavailability, determinants

Relative bioavailability determinations are limited by what is known about the quantitative absorption of the reference substance. One cannot confidently predict absorption of the test substances based on relative bioavailability data. Relative bioavailability data, however, can be used to rank the test sources and to provide a basis for comparison among experiments. 

The human genome contains nearly 900 genes that encode transporters, of which over 300 are intracellular transporters [1] responsible for transporting a wide range of molecules across the membrane [2]. Further classification of these transporters into families such as the solute carrier dass (SLC) [3] and ATP binding cassette (ABC) family 4, 5] is possible. Transporters play a major role in clinical pharmacology as their adequate bioavailability determines the successful oral delivery of many therapeutics. Membrane transporter proteins are associated with drug absorption (uptake), tissue distribution (efflux and uptake), metabolism (hepatic efflux and uptake), and elimination (renal, biliary transporters, and breast milk efflux and uptake) [6, 7]. 

Absolute bioavailability is a measure of the true extent of systemic absorption of an extravascularly administrated drug. Along with clearance and volume of distribution, absolute bioavailability is one of the important parameters to characterize PK. Low bioavailability of a drug can be caused by incomplete dissolution when administrated as a solid, inability to permeate membranes, and metabolic instability (first-pass metabolism). Despite the importance of absolute bioavailability, it is not routinely assessed due to the cost and toxicology requirements for such a study in a conventional study design, which requires an intravenous reference. Safety issues may arise due to solubility limitation and toxicity associated with Cmax effect. As a result, it is necessary to conduct a preclinical toxicological study with an IV formulation to ensure adequate human safety and potential problem. Bioavailability determined from animal models is not always predictive of that in human. 

The transport of the dissolved active substance over the membranes to the blood circulatiOTi is called absorption. The extent and rate of absorption are determined by several factors, including the size and charge of the active substance molecule, its lipophilicity, the volume available for active substance dissolution, the surface and permeability of the absorbing membrane, the presence of metabolising enzymes and, in the case of active transport, the presence of transporters. As a consequence, poor bioavailability may be caused by incomplete dissolutimi of the active substance, by poor permeation over the absorbing membrane, or by metabolism during absorption. 

Klienfeld and Tabershaw 1954 Prout et al. 1985 Stephens 1945 Stevens et al. 1992 Templin et al. 1993 Withey et al. 1983), or dermal (Bogen et al. 1992 Jakobson et al. 1982 McCormick and Abdul-Rahman 1991 Sato and Nakajima 1978 Steward and Dodd 1964 Tsuruta 1978) exposure. All these routes of exposure may be of concern to humans because of the potential for trichloroethylene to contaminate the air, drinking water, food, and soil. More information on the absorption of trichloroethylene following ingestion of contaminated soil and plants grown in contaminated soil near hazardous waste sites are needed to determine bioavailability of the compound in these media. 

The mucosa of the GIT represents an interface between the external and internal environments. The expansive surface area is necessary for the efficient hydrolysis of foodstuffs and the absorption of energy and nutrients. The mucosa also influences the systemic availability of non-nutrient compounds in the diet, both beneficial and detrimental. Digestion and absorption of glucosinolates are critical determinants of health benefits (see Chapter 4) Similarly, the bioavailability and health benefits of phytoestrogens, such as genistein (see Chapters 5 and 10) are at least partly dependent on the carrier-mediated processes of absorption associated with the GIT (Oitate et al, 2001). Moreover, the metabolic activities of the mucosa can influence the systemic concentrations and forms of dietary phytochemicals, as exemplified by research with soy isoflavones (Andlauer et al., 2000). 

In the total plasma response approach, the bioavailability of a compound is determined by measuring its plasma concentration at different times (up to weeks) after single or long-term ingestion of the compound from supplements or food sources. Generally, a plasma concentration-versus-time plot is generated, from which is determined the area-under-curve (AUC) value used as an indicator of the absorption of the componnd. Here, the term relative bioavailability is more appropriate since AUC valnes of two or more treatments are usually compared. This is in contrast to absolnte bioavailability for which the AUC value of the orally administered componnd is compared to that obtained with intravenous administration taken as a reference (100% absorption). 

In contrast with the hydrocarbon carotenes primarily located in the cores of the CM particles, xanthophylls are present at the surfaces of the CM particles, making their exchanges with other plasma lipoproteins easier." Therefore, if some exchanges occur between lipoproteins, AUC (or absorption) values of the newly absorbed compound in the TRL fraction will be underestimated. Based on all these considerations, the present approach is more appropriate to determine the relative bioavailability of a compound derived from various treatments within one snbject and/or within one study. 

Clearance is a critical parameter because of its role in determining a drug s dose size and frequency. First-pass clearance in combination with absorption determines a compound s bioavailability. Clearance and absorption in combination with potency determine dose size. Clearance and volume of distribution determine half-life, and thus dosing frequency. 

In these cases it is not necessary to determine the absolute bioavailability or the absorption rate constant for the product under study. It is only necessary to prove that the plasma concentration versus time curve is not significantly different from the reference product s curve. This is done by comparing the means and standard deviations of the plasma concentrations for the two products at each sampling time using an appropriate statistical test. 

Those aspects critical to the in vivo bioavailability of the product and routine control tests proposed to ensure that the product has consistent bioavailability from batch to batch. Where a product has low in vivo absorption, the evidence should be discussed and a conclusion reached as to whether this is due to intrinsic properties of the active ingredient(s) or whether it is related to the properties of the dosage form concerned. In the case of products intended to have a nonsystemic effect, the potential for systemic absorption may need to be considered. This may involve specific studies to determine the levels of the active ingredient(s) in the blood, plasma, urine, or feces and a discussion of the clinical significance of those results. 

Comer, J. E. A. High-throughput pKa and log P determination, in van de Waterbeemd, H. Lennemas, H. Artursson, P. (eds.), Drug Bioavailability. Estimation of Solubility, Permeability, Absorption and Bioavailability, Wiley-VCH, Weinheim, 2003 (in press). 

The total metal concentration in a solution can be easily determined using methods such as atomic absorption spectroscopy (AAS) however, the bioavailability of different metal species likely varies. In addition, much of the original concentration may have speciated into insoluble precipitates. Therefore, the concentration of some bioavailable species may be extremely low, perhaps even within or below the nanomolar range.99 Ion-selective electrodes are useful for measuring the bioavailable concentration of a metal because they measure only the free, ionic species, which is often most prevalent.102... 

Bioavailability from Environmental Media. Additional information on absorption following dermal contact with, or ingestion of, contaminated soil and water would also be helpful in determining the importance of this route of exposure for populations of concern. 

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