Partitioning into membranes

A CRO may also allow for the in-house introduction of specialized lipophilic scales by transferring routine measurements. While the octanol-water scale is widely applied, it may be advantageous to utilize alternative scales for specific QSAR models. Solvent systems such as alkane or chloroform and biomimetic stationary phases on HPLC columns have both been advocated. Seydel [65] recently reviewed the suitabihty of various systems to describe partitioning into membranes. Through several examples, he concludes that drug-membrane interaction as it relates to transport, distribution and efficacy cannot be well characterized by partition coefficients in bulk solvents alone, including octanol. However, octanol-water partition coefficients will persist in valuable databases and decades of QSAR studies. 

Seydel, J. K., Wiese, M. Octanol-water partitioning versus Partitioning into membranes. In Drug-Memhrane Interactions (Methods and Principles in Medicinal Chemistry), Seydel, J. K., Wiese, M. (eds.), Wiley-VCH, Weinheim, 2002, Vol. 15,... 

Over the years, various tissues and tissue components have been discussed as compartments into which drugs can penetrate and bind. The ability of lipophilic drugs to partition into membranes has been known for many years, especially cationic drugs that can bind to anionic phospholipid membranes [15-20]. The phenomenon of lysosomal trapping has also been cited as a factor that contributes to the tissue binding and high VD values of weakly basic drugs [20-23]. 

These trends clearly reveal that chemicals with greater tendencies to partition into membranes require lower concentrations in the culture media to cause... 

Octanol-Water Partitioning versus Partitioning into Membranes... 

Octanol-Water Partition versus Partitioning into Membranes I 37... 

HazardExpert estimates and takes into account the octanol/water partition coefficient (usually abbreviated to log P or logKow) and pKa of the query compound. The octanol-water partition coefficient is a surrogate for partition between water and fatty biological membranes, which has implications for transport of a chemical to its site of action and its capacity to bind at, or interact with, the site. The pKa, a measure of acidity, indicates the readiness of the compound to ionize in solution, which can have a big influence on partition into membranes, since retention of the ionized form in the aqueous phase is likely to be favored. More recently modules that make use of predictions from ANN have been added to the software package available with HazardExpert. 

Nitric oxide has recently been shown to react very rapidly with organic hydroperoxyl radicals (Padmaja and Huie, 1993). This rapid radical-radical addition could account for the ability of nitric oxide to inhibit lipid peroxidation (Rubbo et al., 1995). Given the relatively high lipid solubility of nitric oxide, it could readily partition into membranes, where it would be sequestered from reactive species such as superoxide and remain for longer periods to act as a chain terminator of radical-mediated lipid peroxidation. Virtually any radical species formed in or near the lipid bilayer could react with nitric oxide (e.g., tocopheryl or ascorbyl radicals) to give nitrosated intermediates or products which could in turn act as nitric oxide reservoirs. 

In this chapter we describe more advanced topics in quenching. Quenching in membranes is desoibed in some detail because of the numerous applications. These include localization of membrane-bound probes, estimation of diffusion coefficients in membranes, and the effect of quencher partitioning into membranes. We also describe transient effects in quenching, which result in nonexponential decays whenever diffusive quenching occurs. These effects can complicate the interpretation of the time-resolved data, but they also provide additional information about the diffusion coefficient of die quencher, the interaction radius, and the medianism of quendiing. For those interested in an introduction to fluorescence, the reading of this chi ter can be postponed. 

During the past 15 years, there have been numerous studies of quenching in membranes. These experiments had a number of goals, including determination of the accessibility of probes to water- and lipid-soluble quenchers, determination of quencher partitioning into membranes, localization of probes in membranes relative to the lipid-water interface, and measurement of lateral diffusion co-... 

CI-976, 2,2-methyl-N-(2,4,6,-trimethoxyphenyl)dodecanamide, (C23H39 NO4, molecular weight 393.57) (Fig. 1) is a white powder that can be stored at room temperature or 4° in a light tight container for at least 1 year. CI-976 is insoluble in water but soluble in ethanol to 50 mM or DMSO to 100 mM. CI-976 is hydrophobic and is highly partitioned into membranes (Homan and Hamelehle, 2001). Stock solutions, generally 25-50 mM, should be stored tightly sealed at -0° or below and used within one month. 

Epand RM, Thomas A, Brasseur R, Epand RF. Cholesterol interaction with proteins that partition into membrane domains an overview. Subcell Biochem. 2010 51 253-278. 

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