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Modeling Exposure
Published in Samuel C. Morris, Cancer Risk Assessment, 2020
The quasiequilibrium models are simple in structure but highly data dependent. Concentration factors are estimated in laboratory studies or are derived from ratios of average concentrations of pollutants in the different “compartments” in the field, sometimes taken from unrelated references in the literature (Kaye et al., 1984). Even given this liberal approach to derivation of the parameters for food chain models, the necessary data are often not available for specific chemical contaminants. In these cases, parameters are estimated from correlations with physicoch-emical properties. One such property is the octanol/water partition coefficient (Kow). This is the ratio of a chemical’s concentration in the octanol phase to its concentration in the aqueous phase of a two-phase octanol-water system. Travis et al. (1986) report relationships between Kow and several food chain parameters, based on regression analysis, which they derive from various sources. The distribution coefficient (Kd), the ratio of the concentration in the soil to the concentration in the solute at equilibrium (similar to the Kd in groundwater models), is used in estimating soil concentrations which, in turn, are used to determine plant uptake from soil. It is related to Kow as:
Liposomes in the Delivery Of Antisense Oligonucleotides
Published in Danilo D. Lasic, LIPOSOMES in GENE DELIVERY, 2019
Some of the chemically modified oligonucleotides are neutral and can bind to the liposome surface via hydrophobic forces. In general, however, such a state of association is not very stable and it is unlikely that these molecules would remain with liposomes after parenteral delivery in vivo. In vitro, where dilution may not be too large upon application to the cell culture, a part (n) of originally associated molecules (N) may remain on the surface, accordingly to the distribution coefficient and the ratios of volumes
Modified-Release Delivery Systems
Published in Larry L. Augsburger, Stephen W. Hoag, Pharmaceutical Dosage Forms, 2017
where J or Mt/M∞ indicates that the fraction of drug released with time is proportional to the surface area A, the diffusion coefficient D, the distribution coefficient K of the permeant toward the polymer, and Δc is the concentration difference across the membrane having thickness L. Therefore, alteration of polymer in terms of type, molecular weight, and degree of crystallinity coupled with membrane thickness and drug properties can give rise to the desired drug release. Equations of similar form can be written for other geometries such as spheres, cylinders, or multi-laminates. Graphic representations for pellets or matrices with different properties that are routinely encapsulated in hard shell capsules for extended release are shown in Figure 12.12.
Today’s drug discovery and the shadow of the rule of 5
Published in Expert Opinion on Drug Discovery, 2023
Since 1997, the landscape of measuring and predicting lipophilicity has changed markedly. The Ro5 was formulated based on observations around the Pomona/Daylight C log P algorithm, which still sets standards in log P prediction based on assiduous curation and updates on contributing fragments. Many other predictors of the partition coefficient are available, such that a cliche of drug discovery is that to become Ro5 ‘compliant,’ you could achieve this by utilizing a different predictor. Measuring log P using high-throughput methods is now routine. Yet, there is an omission in this analysis, namely, the impact of charge in molecules and the importance of the distribution coefficient (log DpH) rather than log P in determining behavior [31]. Furthermore, with large molecules in particular, the role of chameleonic behaviors when different ‘faces’ of a compound can be unveiled depending on environment and intramolecular hydrogen bonding [32] is increasingly appreciated [33]. This ‘effective’ lipophilicity is what drives interactions and is shown to be more important in practice [34]. Reducing lipophilicity with charge [35] brings its own potential issues in terms of increased volume of distribution, increased toxicity risk and potential phospholipidosis for bases [36] or higher protein binding and poorer permeability with acids [37].
Factors determining the oral absorption and systemic disposition of zeaxanthin in rats: in vitro, in situ, and in vivo evaluations
Published in Pharmaceutical Biology, 2022
Seong‑Wook Seo, Dong‑Gyun Han, Eugene Choi, Min‑Jeong Seo, Im‑Sook Song, In‑Soo Yoon
The lipophilicity, solubility, plasma protein binding, blood distribution, and biological stability of zeaxanthin were determined as described in our previous study (Han et al. 2021). The distribution coefficient (log D) was measured in buffers of varying pH values (pH 1.0, 3.0, 5.0, 7.0, 9.0, and 11.0). The SGF and SIF used in the solubility and stability tests were prepared as follows: SGF was prepared by dissolving 0.32% (w/v) pepsin, 0.2% (w/v) sodium chloride, and 0.7% (v/v) HCl in DW (final pH = 1.2); SIF was prepared by dissolving 0.1% (w/v) pancreatin and 3 mM sodium taurocholate in phosphate buffer (final pH = 7.0). The solubility of zeaxanthin (2 μM) was measured in buffers of varying pH values (pH 1.0, 3.0, 5.0, 7.0, 9.0, and 11.0), plasma, phosphate buffer saline, SGF, and SIF. The unbound fraction in plasma (fuP) and the blood‑to‑plasma concentration ratio (RB) were determined at a zeaxanthin concentration of 2 μM. The stability of zeaxanthin (2 μM) was determined in several matrices, including buffers of varying pH values (pH 1.0, 3.0, 5.0, 7.0, 9.0, and 11.0), plasma, urine, SGF, and SIF.
Liposomes as vehicles for topical ophthalmic drug delivery and ocular surface protection
Published in Expert Opinion on Drug Delivery, 2021
José Javier López-Cano, Miriam Ana González-Cela-Casamayor, Vanessa Andrés-Guerrero, Rocío Herrero-Vanrell, Irene Teresa Molina-Martínez
The ability of drugs to cross the cornea is conditioned by the size and the distribution coefficient of the active substance. The higher the diffusion coefficient, the greater the importance of the transcellular pathway. For values of distribution coefficient between 0,01–10, the pass through the lipophilic epithelium and endothelium becomes more viable. When the value is higher than 10, almost all the passage occurs through the transcellular route and the stroma becomes the limiting barrier. This is the reason why when the distribution coefficient is too large the permeability stops increasing. However, in the case of solutes with a low distribution coefficient, that is, substances with a hydrophilic nature, the main impediment is the epithelium and the main passage through the cornea is the paracellular route. In this sense, the passage of hydrophilic substances depends on their size or molecular weight, being this process easier for small solutes with a molecular weight less than 500 Da, and especially difficult for macromolecules [71–74]. After penetration through the cornea, the drug will reach the intraocular tissues. First, the drug reaches the aqueous humor, from where it will pass to the intraocular tissues of the anterior segment. By this way, the drug will have to go through the anterior segment to reach the posterior segment [75].