Lipophilicity Determination Using Liposomes

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Lombardo F, Shalaeva MY, Tupper KA et al. (2001) A tool for lipophilicity determination in drug discovery. 2. Basic and neutral compounds. J Med Chem 44 2490-2497 Nasal A, Siluk D, Kahszan R (2003) Chromatographic retention parameters in medicinal chemistry and molecular pharmacology. Curr Med Chem 10 381—426 OECD (1989) Guideline for testing of chemicals 117, (http //www.oecd.org) 

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The use of partition coefficients between water and lipophilic media is of wide use in pharmaceutical research. As discussed in the last chapters, different lipophilicity scales are used to describe the lipophilicity of a compound and relate it to its absorption behaviour in vivo. Differences between the logPow and partitioning between phospholipids and water (mainly determined using liposomes) for diverse compounds have been described leading to the development of the immobilized artificial membrane chromatography system. However, also the predictivity of the IAM system is limited and only a small number of membrane systems are available. 

Less frequently used at present is electron spin resonance spectroscopy, which is based on the use of spin probes as model componnds or covalent spin labeling of drugs. Microviscosity and micropolarity of the molecnlar environment of the probe can be derived from electron spin resonance spectra. Moreover, the spectra allow us to differentiate isotropic and anisotropic movements, which result from the incorporation of the probe into liposomal structures. Quantitative distribution of the spin probes between the internal lipid layer, the snrfactant, and the external water phase is to be determined noninvasively. On the basis of the chemical degradation of drugs released from the lipid compartment, agents with reductive features (e.g., ascorbic acid) allow us to measure the exchange rate of the drugs between lipophilic compartments and the water phase [27,28]. 

Transport into Liposomes. Most recently, we have begun liposome influx studies using radiolabeled sugars. We have found that lipophilic arylboronic acids can facilitate sugar transport into empty liposomes. Figure 8 shows some typical preliminary results. C-labeled liposomes were treated with H-labeled glucose in the presence and absence of boronic acids. Every ten minutes an aliquot was removed and the amount of glucose associated with the liposomes (ratio of Glu PL) was determined 24). 

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