Human Bioavailability

PTMs-contaminated soils pose a human health risk on the basis of the potential of the contaminant to leave the soil and enter the human bloodstream. In order to assess human health risk, several pathways of transfer of metals from soil to humans have to be taken into account. The most important metal intake takes place via the food chain in which plants or meat of animal play a key role. The direct ingestion of soil can be a major route of exposure for humans to many low mobile soil contaminants, particularly for small children through putting hands into the mouth (Gupta et al., 1996). The contribution from the inhalation of particles smaller than 10 pm and from dermal contact with soil have little meaning compared with oral ingestion and are found to be less than 1% and 0.1% of the total intake, respectively (Paustenbach, 2000). 

Oral bioavailability of soil-borne contaminants is defined as the contaminant fraction that reaches systemic circulation and derives from the combined result of soil ingestion, bioaccessibility, absorption and the first-pass effect (Fig. 9.4) (Oomen et al., 2003 Wragg and Cave, 2003). The bioaccessible fraction is defined as the contaminant fraction that is mobilised from soil into the digestive juice chyme and represents the maximum amount of contaminant available for intestine absorption (Ruby et al., 1996, 1999). 

Bioaccessibility, and therefore oral bioavailability of soil contaminants, depends on soil type and contaminant (Davis et al., 1997 Gr0n and Anderson, 2003 Hamel et al, 1998 Ruby et al., 1999). PTMs occur in soil as a complex mixture of solid-phase chemical compounds of varying particle size and morphology, characterised by variable metal bioavailability. Mineral phases that form under acidic conditions (e.g. lead sulphate, iron-lead sulphate) will tend to be more stable in the acidic conditions of the stomach and hence less bioaccessible. By contrary, mineral phases 

Model Simulated compartments Extractants Tested elements References 

RIVM Stomach Small intestine Oral cavity Gastric juice (pepsin, mucin), pH 2 Intestinal juice (porcine bile, trypsin, pancreatine), pH 7.5 Saliva, pH 6.5 Pb, Cr, Hg As, Cd, 5, 10 

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All piroxicam batches were manufactured in compliance with Good Manufacturing Practices, and three formulations having fast, moderate, and slow dissolution were chosen for comparison to a lot of the innovator s product in a human bioavailability study [100]. The resulting pharmacokinetic data provided still another opportunity to examine the effects of formulation variables. To explore the relationship between the in vitro dissolution of piroxicam from these capsules and in vivo absorption, Polli [ 102] used the following previously described [145] deconvolution-based model ... 

As previously noted, the bioavailability of a compound is a complex function that includes contributions from absorption and clearance. Since the molecule must undergo these biological processes in all species, there is a temptation to assume a relationship between the bioavailability between species, and hence that human bioavailability can be predicted by such relationships. Although a linear correlation has been demonstrated for the rate/extent of absorption (% oral dose absorbed) between species for various drugs [6-8], there is clearly a lack of correlation for bioavailability between species [2, 8]. Figure 19.1 shows the excellent correlation in... 

In the first example, the predicted oral absorption for a series of ACE inhibitors has been compared with published values of human bioavailability. For the generation of calculated absorption, a sigmoidal curve between observed human absorption and PSA for a series of reference compounds was used [25], The predicted oral absorption for ACE inhibitors is plotted against the calculated PSA values is shown in Fig. 19.6 however, as expected, only a partial correlation existed between predicted absorption and observed in vivo bioavailability. 

Fig. 19.8. Prediction of human bioavailability from calculated human absorption using polar surface area (PSA) for a series of calcium antagonists [25],...

Obach et al. [27] proposed a model to predict human bioavailability from a retrospective study of in vitro metabolism and in vivo animal pharmacokinetic (PK) data. While their model yielded acceptable predictions (within a factor of 2) for an expansive group of compounds, it relied extensively on in vivo animal PK data for interspecies scaling in order to estimate human PK parameters. Animal data are more time-consuming and costly to obtain than are permeability and metabolic clearance data hence, this approach may be limited to the later stages of discovery support when the numbers of compounds being evaluated are fewer. 

Approximately 300 drugs were tested in aqueous solubility, log D, apparent permeability and metabolic stability assays. Compounds having low values for solubility, apparent permeability, or metabolic stability, or extreme log D values were flagged. The frequency of compounds with flags in each human bioavailability (%) bin is shown. 

Human pharmacokinetics and bioavailability section. A section describing the human pharmacokinetic data and human bioavailability data, or information supporting a waiver of the submission of in vivo bioavailability data under subpart B of part 320, including the following ... 

Speciation science seeks to characterise the various forms in which PTMs occur or, at least, the main metal pools present in soil. This chapter provides a review of the single and sequential chemical extraction procedures that have been more widely applied to determine the plant and the human bioavailability of PTMs from contaminated soil and their presumed geochemical forms. Examples of complementary use of chemical and instrumental techniques and applications of PTMs speciation for risk and remediation assessment are illustrated. 

More widely applied to determine the potential, plant and human bioavailability are the methods of PTMs speciation which involve selective chemical extraction techniques. Estimation of the plant- or human-available element content of soil using single chemical extractants is an example of functionally defined speciation, in which the function is plant or human availability. In operationally defined speciation, single extractants are classified according to their ability to release elements from specific soil phases. Selective sequential extraction procedures are examples of operational speciation (Ure and Davidson, 2002). 

This chapter provides a review of the single and sequential chemical extraction procedures that have been more widely applied to estimate the plant and the human bioavailability of PTMs from contaminated soil and their presumed geochemical forms. 

Several scientific studies provide evidence of the traditional use of parsley in medicine. Food plants of the Apiaceae plant family such as parsley, carrots and celery contain a group of bioactive aliphatic C17-polyacety-lenes, which were shown to be highly toxic towards fungi, bacteria and mammalian cells and to display neurotoxic, anti-inflammatory and antiplatelet aggregatory effects and to be responsible for allergic skin reactions in a study by Christensen and Brandt (2006). The effect of these polyacetylenes towards human cancer cells, their human bioavailability and their ability to reduce tumour formation in a mammalian in vivo model indicate that they may be beneficial for health. 

Table 6.1 Dose and human bioavailability data of NSAIDs [227].

Bates C and Heseker H (1994) Human bioavailability of vitamins. Nutrition Research Reviews 7,93-128. 

Maximal enrichment of plant tissues with stable isotopes would occur if the mineral in the nutrient solution were totally replaced with the stable isotope throughout the entire growing period. However, this would not be the most efficient use of stable isotopes and could be prohibitively expensive for some stable isotpes such as Zn in quantities needed for a human bioavailability study. 

Acetaminophen. The effect of aging of the solid dispersion of acetaminophen in PEG-20,000 on human bioavailability was studied. It was found that the bioavailability of the sample stored... 

Hata, T. Shimazaki, Y. Kagayama, A. Tamura, S. Ueda, S. Development of a novel drug delivery system (TES) V. Animal pharmacodynamic study and human bioavailability study. Int. J. Pharm. 1994,110, 1-7. 

Fig. 6 Graphical representation of correlation between human bioavailability data for a series of known drugs and Caco-2 cellular permeability data (Papp coefficient). (This data is obtained with permission from AstraZeneca, 1998.)...

For extended-release dosage forms, in vitro-in vivo correlation may be used to establish acceptance criteria when human bioavailability data are available for formulations exhibiting different release rates. Where such data are not available, and drug release cannot be shown to be independent of in vitro test conditions, then acceptance criteria should be established on the basis of available batch data. Normally, the permitted variability in mean release rate at any given time point should not exceed a total... 

Figure 16.2 Plot of the absolute human bioavailability of various drugs versus their absolute bioavailability in primates, dogs, and rodents [19].

Another approach to human bioavailability estimation is based on in vitro data using Caco-2 as a measure of permeability and human liver microsomes for metabolism estimates. These data are combined in a graphical method to get a rough estimate of human oral bioavailability [22]. In principle, but not yet proven, this method could also be applied by using calculated permeability and metabolic stability. 

One of the earliest in silico models of human bioavailability was reported by Hirono and coworkers [26]. This study employed a set of 188 compounds that were classified as low (<50%), medium (50-89%), or well (>90%) absorbed and used a classification routine, fuzzy adaptive least squares, to generate discriminant functions. The molecules were described by their physicochemical properties and substructural descriptors, which meant that functional groups or substructures that enhanced bioavailability (e.g., saturated carbon atoms in side chains) or reduced it (e.g., aliphatic hydroxyl groups) could be identified. The performance varied between the three classes with the lowest success for the well-absorbed compounds, perhaps the most important group of the three. 

Given the relatively poor performance of quantitative models, it is not surprising that other attempts to build in silico models of human bioavailability have concentrated on classification. Adaptive fuzzy partitioning (AFP) was applied for two sets of bioavailability data subdivided into four ranges of activity [31]. The best models using... 

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