Lipophilicity models

Our present topic is the relationship between permeability and lipophilicity (kinetics), whereas we just considered a concentration and lipophilicity model (thermodynamics). Kubinyi demonstrated, using numerous examples taken from the literature, that the kinetics model, where the thermodynamic partition coefficient is treated as a ratio of two reaction rates (forward and reverse), is equivalent to the equilibrium model [23], The liposome curve shape in Fig. 7.20 (dashed-dotted line) can also be the shape of a permeability-lipophilicity relation, as in Fig. 7.19d. 

A lipophilicity model based on atomic charges, surface areas, dipole moments, and a set of adjustable parameters depending only on the atomic number [Kantola et al., 1991]. The parameter values are determined in order to reproduce experimental logP values using the following general model ... 

Miihlebach S, Bickel MH. 1981. Pharmacokinetics in rats 2,4,5,2 ,4, 5, -hexachlorobiphenyl, an unmetabolizable lipophilic model compound. Xenobiotica 11(4) 249-257. 

Kreilgaard, M., Kemme, M.J.B., Burggraaf, J., Schoemaker, R.C. and Cohen, A.F. (2001) Influence of a microemulsion vehicle on cutaneous bioequivalence of a lipophilic model drug assessed by microdialysis and pharmacodynamics. Pharm. Res., 18, 593-599. 

This chapter will discuss (a) the production and characterization of LS formed by the melt dispersion technique, by the solvent evaporation method, and by the water/oil/water (w/o/w) double-emulsion method (b) the influence of preparation parameters on liposphere morphology and (c) the encapsulation efficiency and the release characteristics of two lipophilic model drugs, such as retinyl acetate and progesterone, and one hydrophilic drug, sodium cromoglycate (SCG), from the prepared LS. 

The lipidic mixture, both with and without a lipophilic model drug, was melted at 70°C and then emulsified into an external aqueous phase containing a suitable surfactant. The emulsion was mechanically stirred by a stirrer equipped with alternative impellers. Afterward, the emulsion was heated to the same temperature as the melted lipidic phase. The milky formulation was then rapidly cooled to about 20°C by immersing the formulation flask in a cool water bath without stopping the... 

By structural complementarity, dicationic l,4-diazabicyclo[2.2.2]octane (VII) provides an appropriate recognition site for phosphate ions and two stearyl side chains attached to the amines add lipophilic properties 59,60). Such a carrier model can selectively extract nucleotides from aqueous solution to chloroform solution via lipophilic salt formation. The order of nucleotide affinity is ATP > ADP > AMP. The selectivity ratios were 45 for ADP/AMP and 7500 for ATP/AMP at pH 3. The relative transport rate was ATP > ADP > AMP. The ratios were 60 for ATP/AMP and 51 for ADP/AMP. The modes of interaction of ADP and ATP are proposed to be as shown in Fig. 6. 

The for the substrate UTP has been measured and does not show significant differences between wt and mutant enzymes. The model shows that the space available to substituents in positions 4 and 5 of the thiophene is limited, in agreement with SAR studies. Interaction with a number of basic and lipophilic residues bound... 

A formidable array of compounds of diverse structure that are toxic to invertebrates or vertebrates or both have been isolated from plants. They are predominately of lipophilic character. Some examples are given in Figure 1.1. Many of the compounds produced by plants known to be toxic to animals are described in Harborne and Baxter (1993) Harborne, Baxter, and Moss (1996) Frohne and Pfander (2006) D Mello, Duffus, and Duffus (1991) and Keeler and Tu (1983). The development of new pesticides using some of these compounds as models has been reviewed by Copping and Menn (2000), and Copping and Duke (2007). Information about the mode of action of some of them are given in Table 1.1, noting cases where human-made pesticides act in a similar way. 

The compounds featured in Table 1.1 are considered briefly here. Pyrethrins are lipophilic esters that occur in Chrysanthemum spp. Extracts of flower heads of Chrysanthemum spp. contain six different pyrethrins and have been used for insect control (Chapter 12). Pyrethrins act upon sodium channels in a manner similar to p,p -DDT. The highly successful synthetic pyrethroid insecticides were modeled on natural pyrethrins. 

L. B. Kier and C.-K. Cheng, A cellular automata model of partitioning between liquid phases. In Lipophilicity in Drug Research, Pliska, Testa, and Waterbeemd, eds., VCH Publ., 1996. 

In this section we describe a cellular automata model of a semipermeable membrane separating two compartments [5]. A solute in one compartment has varied parameters to reflect its relative polarity or lipophilicity. The passage of this solute into and through the membrane is observed, as this property is varied. 

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