In determining bioavailability

This model integrates existing in vitro data, such as Caco-2 permeability (Papp) and metabolic stability in liver S9 or microsomes, to estimate bioavailability as being either low, medium, or high. Oral bioavailability predictions for not only humans but also other species can be made by using the metabolic stability values of drugs in liver microsomal enzyme preparations from that species. A premise of this model is that metabolic clearance is more important than renal or biliary clearance in determining bioavailability. However, despite the lack of in vitro renal... 

Given the overwhelming influence of the physical properties of skin in determining bioavailabilities via the dermal route, assessment of dermal penetration is one area in metabolism and toxicology where in vitro methods can be effectively used to predict in vivo results and to screen chemicals. Apparatus and equipment exist that one can use to maintain sections of skin (obtained from euthanized animals or from human cadavers or surgical discard) for such experiments (Holland et al., 1984). These apparatus are set up to maintain the metabolic integrity of the skin sample between two reservoirs the one on the stratum comeum side, called the application reservoir and the one on the subcutaneous side, called the receptor reservoir. One simply places radiolabeled test material in the application reservoir and collects samples from the receptor fluid at various time points. 

This chapter provides basic information on the physicochemical mechanisms of drug absorption and how the processes of absorption are affected by the physicochemical properties of the drug and its formulation, by the interaction of the drug with the aqueous phase and by the nature of the membrane. Oral absorption is discussed in some detail and the influence of the following in determining bioavailability should become clear ... 

Soil properties (edaphic factors) are important in determining bioavailability and include nutrient status, organic-matter content, soil structure, temperature, moisture and pH (Weber et al. 1993). Ageing is another important edaphic factor, because it appears that the amount of extractable contaminant decreases over time. For example, 8-14% of 14C-labelled 1,3,6,8-TCDD was found to become unextractable in soil after about a year in one study (Muir et al. 1985). It seems that a contaminant will diffuse into kinetically remote compartments of soil over time. It is possible, therefore, to distinguish three contaminant fractions a labile, relatively bioavailable fraction a recalcitrant, relatively firmly bound but still extractable fraction and a non-extractable, irreversibly bound fraction (Jones et al. 

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. 

Xenobiotics exist not only in the free state but also in association with organic and mineral components of particles in the water mass, and the soil and sediment phases. This association is a central determinant of the persistence of xenobiotics in the environment, since the extent to which the reactions are reversible is generally unknown. Such residues may therefore be inaccessible to microbial attack and apparently persistent. This is a critical factor in determining the effectiveness of bioremediation (Harkness et al. 1993). Although the most persuasive evidence for the significance of reduced bioavailability comes from data on the persistence of agrochemicals in terrestrial systems (Calderbank 1989), the principles can be translated with modification to aquatic and sediment phases that contain organic matter that resembles structurally that of soils. 

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. 

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. 

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. 

The use of hepatic portal vein-cannulated animals can be helpful in determining specific causes of poor bioavailability. After oral dosing, the total bioavailability of a compound is normally calculated as ... 

The liver plays an important role in determining the oral bioavailability of drags. Drag molecules absorbed into the portal vein are taken up by hepatocytes, and then metabolized and/or excreted into the bile. For hydrophilic drugs, transporters located on the sinusoidal membrane are responsible for the hepatic uptake [1, 2]. Biliary excretion of many drags is also mediated by the primary active transporters, referred to as ATP-binding cassette transmembrane (ABC) transporters, located on the bile canalicular membrane [1, 3-5], Recently, many molecular biological... 

The Importance of Cut Wall Metabolism in Determining Drug Bioavailability... 

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