Bioavailability number

A simplified dimensional analysis can aid in interpreting our results. Dimensionless numbers are often used to generalize, scale-up, and compare results from one system to another. In the context of this study, a useful parameter is the bioavailability number, Nb (20), which is simply the ratio of the rate of mass transfer to the rate of biodegradation ... 

A bioavailability number less than unity indicates that the biological transformation of a contaminant in a system is limited by its mass transfer from the soil/sediment. Conversely, a bioavailability number greater than unity... 

In the field, parameters used in the bioavailability number may be difficult to quantify due to mixed populations of microorganisms, heterogeneous soil samples, and variable moisture conditions and exposure times. However, under controlled experimental conditions, this simplified analysis allows quantification and a relative measure of the effects of experimental variables, e.g. soil type and aging conditions. 

This analysis indicates that the rate of mass transfer is the rate-limiting step for each soil type. This explains why the desorption and mineralization profiles were qualitatively similar. The difference in time scales may likely be due to the experimental design the mineralization experiment only detected complete mineralization and did not detect the initial biodegradation to intermediate metabolites while the desorption experiment measured all phenanthrene that desorbed. The bioavailability number analysis shows that for each soil, the desorption resistant fraction has a bioavailability number that is several orders of magnitude lower than that of the labile fraction. This implies that although a... 

Of course there are several factors not explored in the bioavailability analysis, for example the soil to solution ratio. Previous investigators have shown that a soil to solution ratio of 1 10 is optimal for microbial degradation (S,9). In addition, the use of a microorganism that had been acclimated to phenanthrene clearly favored the case of a mass-transfer limited system. However, the use of the dimensionless bioavailability number will allow comparison for different cases in future work. 

Traditionally, in pursuit of their structure-activity relationships, medicinal chemists had focused almost exclusively on finding compounds with greater and greater potency. However, these SARs often ended up with compounds that were unsuitable for development as pharmaceutical products. These compounds would be too insoluble in water, or were not orally bioavailable, or were eliminated too quickly or too slowly from mammalian bodies. Pharmacologists and pharmaceutical development scientists for years had tried to preach the need for medicinal chemists to also think about other factors that determined whether a compound could be a medicine. Table 1.1 lists a number of factors that determine whether a potent compound has what it takes to become a drug. Experimentally, it was difficult to quantitate these other factors. Often, the necessary manpower resources would not be allocated to a compound until it had already been selected for project team status. 

A number of factors described as influencing carotenoid bioavailability were regrouped under the SLAMENGFll mnemonic. Species of carotenoid. Linkages at molecular level. Amount of carotenoids consumed in a meal. Matrix in which the carotenoid is incorporated. Effectors of absorption and bioconversion. Nutrient status of the host. Genetic factors. Host-related factors, and Interactions among these variables. Only the factors that affect the micellarization of the compound in the gut are discussed and summarized in Table 3.2.1. 

In order to exhibit provitamin A activity, the carotenoid molecule must have at least one unsubstituted p-ionone ring and the correct number and position of methyl groups in the polyene chain. Compared to aU-trans P-carotene (100% provitamin A activity), a-carotene, P-cryptoxanthin, and y-carotene show 30 to 50% activity and cis isomers of P-carotene less than 10%. Vitamin A equivalence values of carotenoids from foods have been recently revised to higher ratio numbers (see Table 3.2.2) due to poorer bioavailability of provitamin A carotenoids from foods than previously thought when assessed with more recent and appropriate methods. 

A series of soil microcosms were used to study the biodegradation and bioavailability of pyrene during long-term incubation. The nonextractable fraction of -labeled pyrene that had been introduced into pristine soil and incubated with or without the addition of azide was substantially greater in the latter (Guthrie and Pfaender 1998). It was also shown that microbial activity produced a number of unidentified polar metabolites that might plausibly be involved in the association. 

From an analysis of the key properties of compounds in the World Dmg Index the now well accepted Rule-of-5 has been derived [25, 26]. It was concluded that compounds are most Hkely to have poor absorption when MW>500, calculated octanol-water partition coefficient Clog P>5, number of H-bond donors >5 and number of H-bond acceptors >10. Computation of these properties is now available as a simple but efficient ADME screen in commercial software. The Rule-of-5 should be seen as a qualitative absorption/permeabiHty predictor [43], rather than a quantitative predictor [140]. The Rule-of-5 is not predictive for bioavail-abihty as sometimes mistakenly is assumed. An important factor for bioavailabihty in addition to absorption is liver first-pass effect (metaboHsm). The property distribution in drug-related chemical databases has been studied as another approach to understand drug-likeness [141, 142]. 

The list of elements and their species listed above is not exhaustive. It is limited to the relatively simple compounds that have been determined by an important number of laboratories specializing in speciation analysis. Considering the economic importance of the results, time has come to invest in adequate CRMs. There is a steadily increasing interest in trace element species in food and in the gastrointestinal tract where the chemical form is the determinant factor for their bioavailability (Crews 1998). In clinical chemistry the relevance of trace elements will only be fully elucidated when the species and transformation of species in the living system have been measured (ComeUs 1996 Cornelis et al. 1998). Ultimately there will be a need for adequate RMs certified for the trace element species bound to large molecules, such as proteins. 

Casein-derived phosphorylated peptides are believed to enhance the bioavailability of calcium from milk and dairy products (Pihlanto and Korhonen, 2003), and a phosphopeptide derived from (3-casein has been shown to increase iron bioavailability (Bouhallab et ah, 2002 Peres, 1999). Other casein-derived peptides have been found to contain antihypertensive activity in rats (Leclerc et ah, 2002 Miguel et ah, 2009). A number of casein fragments demonstrate antibacterial activity (Kilara and Panyam, 2003). 

The search for an effective non-peptide oxytocin antagonist has become a major goal of a number of pharmaceutical companies because of the poor pharmacokinetic properties and especially the lack of oral bioavailability associated with peptidic antagonists. Early research in this field was dominated by Merck, but in recent years significant research efforts at GlaxoSmithKline and Serono have been published. A number of other companies, notably Sanofi-Aventis, Yamanouchi and Wyeth, have had a major presence in vasopressin receptor research and oxytocin is frequently included in patent claims for the molecules. Occasionally, oxytocin-selective compounds have been reported, usually derived by adaptation of the vasopressin antagonist template. 

In the discovery phase, a reaction route is developed to allow synthesis of a maximum number of analogues for pharmacological testing. Since the focus is on synthetic flexibility, issues of scale are not central. Once a lead compound exhibits a useful pharmacological activity and is identified as a candidate for further development, larger scale synthesis is required to evaluate stability, bioavailability, toxicity, physicochemical properties, and other compound properties. The Chemical Development Department is usually involved in the preparation of supplies for these activities. 

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