Properties Affecting Bioavailability

Exposure is highly dependent on the bioavailability of the chemical to organisms. The more bioavailable a substance is, the more likely it is that there will be adverse effects 

Bioconcentration BCF Accumulation from the matrix into the organism (aquatic organisms only) 

Biomagnification BMF Accumulation from the food into the organism 

Bioaccumulation BAF Accumulation from the matrix and food into the organism 

Bioaccumulation from sediment BSAF Accumulation from the food, water, and sediment into the organism 

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The physical characteristics should be considered (in combination as appropriate) in relation to the proposed dosage form and route of administration. Factors to be considered extend to solubility characteristics, crystal form and properties, moisture or solvent content, particle size and size distribution (which may affect bioavailability, content uniformity, suspension properties, stability, and preclinical or clinical acceptability), polymorphism, etc. 

A thorough understanding of the hydration profile for a solid forming a crystal hydrate is important for several reasons. First, since an anhydrate and hydrate(s) are distinct thermodynamic species, they will have different physical-chemical properties (e.g., solubility) that may affect bioavailability. Second, a desired hydrate species can be formed and used (and retained) simply by controlling the desired, established environmental conditions. Third, since significant quantities of water can be sorbed/liberated as a hydrate becomes hydrated/dehydrated, the physical-chemical properties of the immediate system (including other nearby solids) can be markedly affected. 

As with clearance, the physicochemical properties of a drug can determine its absorption and hence affect bioavailability. Hydrophilic drugs may dissolve well in the gut lumen and hence cause few formulation problems, but cross cell membranes poorly and hence may be poorly... 

Water solubility is one of the most important physicochemical properties affecting the potential for exposure and bioavailability of chemical substances. For any substance to be absorbed, it must have sufficient water solubility to achieve a concentration gradient with respect to the cell exterior/interior. Also, to be transported across the cellular membrane, a substance must be in its finest state of molecular disaggregation (Figure 11.2). When in solution, a substance is completely disaggregated. 

Physical / chemical properties affect the rate of biodegradation mostly by affecting bioavailability. Compounds which are sparingly soluble in water tend to be more resistant to biodegradation, possibly due to an inability to reach the microbial enzyme site, a reduced rate of availability due to solubilization, or sequestration due to adsorption or trapping in inert material (Alexander, 1973 Alexander, 1994). 

Soil or water pH is one of the most important parameters when dealing with metal bioavailability. Also for ionizable organic chemicals, like chlorophenols, pH may affect bioavailability. Changes of conditions in environmental compartments may depend on their surrounding environments and climatic changes, and pH is one of those properties that can show larger changes. 

Bioavailability, Bioequivalence, and Pharmacokinetics. Bioavailabihty can be defined as the amount and rate of absorption of a dmg into the body from an adrninistered dmg product. It is affected by the excipient ingredients in the product, the manufacturing technologies employed, and physical and chemical properties of the dmg itself, eg, particle size and polymorphic form. Two dmg products of the same type, eg, compressed tablets, that contain the same amount of the same dmg are pharmaceutical equivalents, but may have different degrees of bioavailabihty. These are chemical equivalents but are not necessarily bioequivalents. For two pharmaceutically equivalent dmg products to be bioequivalent, they must achieve the same plasma concentration in the same amount of time, ie, have equivalent bioavadabihties. 

Another physical property that can affect the appearance, bioavailability, and chemical stability of pharmaceuticals is degree of crystallinity. Amorphous materials tend to be more hygroscopic than their crystalline counterparts. Also, there is a substantial body of evidence that indicates that the amorphous forms of drugs are less stable than their crystalline counterparts [62]. It has been reported, for example,... 

The bioavailability of drugs from tablets can be markedly influenced by the rate and efficiency of the initial disintegration and dissolution process. Unfortunately, one is faced with a compromise situation — a structure that has both a durable structure prior to administration and the ability to readily break down when placed in the in vivo environment. One of the major factors affecting both these properties is the structure of the tablet, in particular its density (or porosity) and the pore structure. Study of the significance of such measurements and interpretation of the results is a relatively recent field of interest. 

This chapter describes some of the properties of solids that affect transport across phases and membranes, with an emphasis on biological membranes. Four aspects are addressed. They include a comparison of crystalline and amorphous forms of the drug, transitions between phases, polymorphism, and hydration. With respect to transport, the major effect of each of these properties is on the apparent solubility, which then affects dissolution and consequently transport. There is often an opposite effect on the stability of the material. Generally, highly crystalline substances are more stable but have lower free energy, solubility, and dissolution characteristics than less crystalline substances. In some situations, this lower solubility and consequent dissolution rate will result in reduced bioavailability. 

In conclusion, phytic acid forms soluble complexes with Ca2+ at intestinal pH under a variety of conditions and fails to inhibit Ca2 bioavailability to mice in our experimental system. Despite the hazard in direct extrapolation of results obtained with animals kept on a well-defined dietary regimen to humans consuming a complex diet, many elements of which affect Ca2+ bioavailability, our data demonstrate the need for a reevaluation of the putative antinutritional properties of dietary phytate. Our further contention that adequate levels of dietary phytate may actually be beneficial due to its food preserving properties and its protection against colonic cancer will warrant a prospective epidemiological human study designed to assess the longterm effects of dietary phytate on mineral bioavailability and inflammatory bowel diseases. 

Polymorphism is critically important in the design of new drug API [9] and affects a number of areas. The main impact is to the bioavailability and release profile of a drug substance into the body. This is due to differences in solubility and dissolution rate, between the polymorphs. The chemical and physical stability of the formulated drug substance is also dependent on the polymorphic form. Patented registration of all discovered forms and their manufacturing conditions is an important element in protecting a pharmaceutical companies intellectual property. 

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