Physicochemical properties, absorption

FIGURE 2.6 The ADME-PK screening data that are obtained in drug discovery and used to determine dosing regimen (i.e., how much and how long ). A combination of assays associated with physicochemical properties (absorption, clearance, and volume of distribution) and PK properties (bioavailability and half life) are used to evaluate each drug candidate. (Courtesy of Milestone Development Services, Newtown, PA. With permission.)... 

Compound optimization in early- and late-phase drug discovery is covered, emphasizing physicochemical properties, in vitro absorption, metabolism and in vivo animal pharmacokinetic methodologies. 

Sometimes, the physicochemical properties of ionic species solubilized in the aqueous core of reversed micelles are different from those in bulk water. Changes in the electronic absorption spectra of ionic species (1 , Co ", Cu " ) entrapped in AOT-reversed micelles have been observed, attributed to changes in the amount of water available for solvation [2,92,134], In particular, it has been observed that at low water concentrations cobalt ions are solubihzed in the micellar core as a tetrahedral complex, whereas with increasing water concentration there is a gradual conversion to an octahedral complex [135],... 

Interesting phenomena are observed by increasing the concentration of reversed micelles, changing the temperature or pressure, applying high electric fields, or adding suitable solutes, In some conditions, in fact, a dramatic increase in some physicochemical properties has been observed, such as viscosity, conductance, static permittivity, and sound absorption [65,80,173,233,243,249,255,264-269],... 

Lipinski et al. at Pfizer [11] analyzed the distribution of physicochemical properties of 2245 drugs from the WDI that have entered clinical trials after excluding natural products and actively transported molecules. They proposed the Rule-of-5 to indicate that poor absorption or permeation is more likely when ... 

Physicochemical properties of the drug product Control and maintenance of the location of the drug product at the absorption site(s)... 

Kimura, Y. Hosoda, Y. Shima, M. Adachi, S. Matsuno, R., Physicochemical properties of fatty acids for assessing the threshold concentration to enhance the absorption of a hydrophilic substance, Biosci. Biotechnol. Biochem. 62, 443 447 (1998). 

The Danish (Q)SAR database is a repository of estimates from over 70 [28] (Q)SAR models for 166,072 chemicals. The (Q)SAR models encompass endpoints for physicochemical properties, fate, ecotoxicity, absorption, metabolism, and toxicity... 

An important part of the optimization process of potential leads to candidates suitable for clinical trials is the detailed study of the absorption, distribution, metabolism and excretion (ADME) characteristics of the most promising compounds. Experience has learned that physico-chemical properties play a key role in drug metabolism and pharmacokinetics (DMPK) [1-3]. As an example, physicochemical properties relevant to oral absorption are described in Fig. 1.1. It is important to note that these properties are not independent, but closely related to each other. 

Sugawara, M., Takekuma, Y., Yamada, H., Kobayashi, M., Iseki, K., Miyazaki, K., A general approach for the prediction of the intestinal absorption of drugs regression analysis using the physicochemical properties and drug-membrane electrostatic interaction, J. Pharm. Sci. 1998, 87, 960-966. 

Orally administered dosage forms are absorbed into the systemic circulation following dissolution in the GI tract. Because substances must be in solution for the absorption from the GI lumen, the absorption rate of poorly water-soluble drugs is limited by their rate of dissolution. The dissolution rate is affected by the unique physicochemical properties of the drug and by physiological factors the pH, composition, and hydrodynamics of the GI medium. 

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