Lipophilicity soluble compounds

An important factor in determining the course of uptake, transport, and distribution of xenobiotics is their polarity. Compounds of low polarity tend to be lipophilic and of low water solubility. Compounds of high polarity tend to be hydrophilic and of low fat solubility. The balance between the lipophilicity and hydrophilicity of any compound is indicated by its octanol-water partition coefficient (K J, a value determined when equilibrium is reached between the two adjoining phases ... 

Xenobiotics are metabolized in two phases. The major reaction of phase 1 is hydroxylation catalyzed by a variety of monooxygenases, also known as the cytochrome P450s. In phase 2, the hydroxylated species are conjugated with a variety of hydrophihc compounds such as glucuronic acid, sulfate, or glutathione. The combined operation of these two phases renders lipophilic compounds into water-soluble compounds that can be ehminated from the body. 

Poorly water-soluble compounds were previously discussed as to the cause of poor water solubility - the large lipophilic greaseballs and the brickdust compounds [15] which are poorly water soluble because of strong intermolecular crystal... 

Wame, M., St. J., Connell, D. W., Hawker, D. W. (1990) Prediction of aqueous solubility and the octanol-water partition coefficient for lipophilic organic compounds using molecular descriptors and physicochemical properties. Chemosphere 16, 109-116. 

The thesis that all lipid-soluble compounds basically penetrate faster than water-soluble ones cannot be supported in this absolute form. A lipophilic agent can penetrate faster or slower or at the same rate as a hydrophilic agent, depending on the vehicle used. 

The division of the intermediates of the reaction pathway into three groups is characteristic CoA compounds, diphosphates, and highly lipophilic, poorly soluble compounds (squalene to cholesterol), which are bound to sterol carriers in the cell. 

The confusion between these two characteristics is common in medicinal chemistry. It comes from the usual empirical measurement of the lipophilicity, which is the logarithm of the partition coefficient between 1-octanol and water (log P). This parameter gives a representative overview of a compound absorbed by a lipidic membrane, an essential datum in medicinal chemistry. It is often considered that the higher the log P value is, the more lipophilic the compound is. Acmally, the log P value is only a measurement of relative solubility. Considering that the solubility of a fluorinated substance decreases more in water than in octanol, this measurement leads one to think that fluorinated compounds are more lipophilic. Actually, this represents the relative lack of affinity of fluorinated compounds for both phases. 

Most psychotropic medications are highly lipophilic. The percentage of total body fat, which is a reservoir for these lipid-soluble compounds, increases during the first year of life and then decreases until the prepubertal increase ( 30). Thus, children at different ages have different volumes of deep storage, which can affect the overall residual time a drug remains in the body after its discontinuation. 

An alternative process that can lead to the termination or alteration of biologic activity is metabolism. In general, lipophilic xenobiotics are transformed to more polar and hence more readily excreted products. The role that metabolism plays in the inactivation of lipid-soluble drugs can be quite dramatic. For example, lipophilic barbiturates such as thiopental and pentobarbital would have extremely long half-lives if it were not for their metabolic conversion to more water-soluble compounds. 

In summary, nasal epithelial intercellular junctions are less restrictive compared to the gastrointestinal tract. Such polar pathways will mainly be responsible for the transport of water-soluble compounds, providing a relatively slow, but significant route which is dependent on the molecular weight of the diffusing species. Secondly, transcellular (lipoidal) pathways permit extremely rapid absorption of lipophilic drugs with a rate dependency based on cell membrane partitioning. 

In another approach, where the 2-methyl carbamate moiety was replaced by a more lipophilic group such as SC02R, SCONR R2 or S(CH2) C02R etc. [33] more soluble compounds were generated. Surprisingly, the resulting compounds exhibited a complete loss of antifilarial activity. It is evident from these studies that the carbamate moiety is an essential pharmacophore for antifilarial activity. 

In addition to their usefulness in the enhancement of oral bioavailability of lipophilic drugs, microemulsion formulations have found considerable application as potential delivery systems for peptides whose delivery is often limited by poor GI permeability. W/O microemulsions provide a convenient means of delivery of both permeability-enhancing lipids and water-soluble peptides. The GI permeability-enhancing effects of lipids and their use in the delivery of highly water-soluble compounds are reviewed elsewhere [18, 56, 59],... 

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