Permeability and Lipophilicity

This refers to the transport across the epithelial cells, which can occur by passive diffusion, carrier-mediated transport, and/or endocytic processes (e.g., transcytosis). Traditionally, the transcellular route of nasal mucosa has been simply viewed as primarily crossing the lipoidal barrier, in which the absorption of a drug is determined by the magnitude of its partition coefficient and molecular size. However, several investigators have reported the lack of linear correlation between penetrant lipophilicity and permeability [9], which implies that cell membranes of nasal epithelium cannot be regarded as a simple lipoidal barrier. Recently, compounds whose transport could not be fully explained by passive simple diffusion have been investigated to test if they could be utilized as specific substrates for various transporters which have been identified in the... 

Knowledge ofthe aqueous ionization constant,pof an ionizable drug candidate is very important because it can be used to predict solubility, lipophilicity, and permeability at different pH therefore, it... 

Figure 22.1 A. Schema for a physiologically based pharmacokinetic model incorporating absorption in the stomach and intestines and distribntion to various tissues. B. Each organ or tissue type includes representation of perfusion (Q) and drug concentrations entering and leaving the tissue. Fluxes are computed by the product of an appropriate rate law, and permeable surface area accounts for the affinity (e.g., lipophilic drugs absorbing more readily into adipose tissue). Clearance is computed for each tissue based on physiology and is often assumed to be zero for tissues other than the gut, the liver, and the kidneys.

Fig. 2.5 Trendships between oral absorption and permeability/lipophilicity. In reality these relationships are most likely sigmoidal, i.e. more complex than these trends indicate.

Octanol-water partition (log P) and distribution (log D) coefficients are widely used to make estimates for membrane penetration and permeability, including gastrointestinal absorption [77, 78], BBB crossing [60, 69] and correlations to pharmacokinetic properties [1]. The two major components of lipophilicity are molecular size and H-bonding [57], which each have been discussed above (see Sections 2.5 and 2.6). 

Lipophilicity is intuitively felt to be a key parameter in predicting and interpreting permeability and thus the number of types of lipophilicity systems under study has grown enormously over the years to increase the chances of finding good mimics of biomembrane models. However, the relationship between lipophilicity descriptors and the membrane permeation process is not clear. Membrane permeation is due to two main components the partition rate constant between the lipid leaflet and the aqueous environment and the flip-flop rate constant between the two lipid leaflets in the bilayer [13]. Since the flip-flop is supposed to be rate limiting in the permeation process, permeation is determined by the partition coefficient between the lipid and the aqueous phase (which can easily be determined by log D) and the flip-flop rate constant, which may or may not depend on lipophilicity and if it does so depend, on which lipophilicity scale should it be based ... 

The coverage of permeability in this book is more comprehensive than that of solubility, lipophilicity, and ionization. This decision was made because permeability is not as thoroughly treated in the pharmaceutical literature as the other topics, and also because much emphasis is placed on the PAMPA in this book, which is indeed a very new technique [547] in need of elaboration. 

Ghosh [548] used cellulose nitrate microporous filters (500 pm thick) as scaffold material to deposit octanol into the pores and then under controlled pressure conditions, displace some of the oil in the pores with water, creating a membrane with parallel oil and water pathways. This was thought to serve as a possible model for some of the properties of the outermost layer of skin, the stratum comeum. The relative proportions of the two types of channel could be controlled, and the properties of 5-10% water pore content were studied. Ibuprofen (lipophilic) and antipyr-ine (hydrophilic) were model drugs used. When the filter was filled entirely with water, the measured permeability of antipyrine was 69 (in 10 6 cm/s) when 90% of the pores were filled with octanol, the permeability decreased to 33 95% octanol content further decreased permeability to 23, and fully octanol-filled filters indicated 0.9 as the permeability. 

The popular permeability equations [(7.10) and (7.11)] derived in the preceding section presume that the solute does not distribute into the membrane to any appreciable extent. This assumption may not be valid in drug discovery research, since most of the compounds synthesized by combinatorial methods are very lipophilic and can substantially accumulate in the membrane. Neglecting this leads to underestimates of permeability coefficients. This section expands the equations to include membrane retention. 

The peculiar depression of metoprolol and quinine permeabilities in 2% DOPC (model 1.0) was not seen in the egg lecithin models. Metoprolol and quinine were significantly more permeable in the lecithins, in line with expectations based on relative octanol-water lipophilicities and relative in vivo absorptions of (3-blockers [593],... 

Lipophilicity and Decrease in Permeability with Increased Phospholipid Content in Dodecane... 

Figures 7.31a-c clearly show that after some critical soy content in dodecane, Pe values decrease with increasing soy, for both sink and sinkless conditions. [This is not due to a neglect of membrane retention, as partly may be the case in Fig. 7.23 permeabilities here have been calculated with Eq. (7.21).] Section 7.6 discusses the Kubinyi bilinear model (Fig. 7.19d) in terms of a three-compartment system water, oil of moderate lipophilicity, and oil of high lipophilicity. Since lipo-some(phospholipid)-water partition coefficients (Chapter 5) are generally higher than alkane-water partition coefficients (Chapter 4) for drug-like molecules, soy lecithin may be assumed to be more lipophilic than dodecane. It appears that the increase in soy concentration in dodecane can be treated by the Kubinyi analysis. In the original analysis [23], two different lipid phases are selected at a fixed ratio (e.g., Fig. 7.20), and different molecules are picked over a range of lipophilicities.

The 20% soy lecithin (Table 7.17) and the 2% DOPC (Table 7.15) intrinsic permeabilities may be compared in a Collander equation, as shown in Fig. 7.44. The slope of the regression line, soy versus DOPC, is greater than unity. This indicates that the soy membrane is more lipophilic than the DOPC membrane. Intrinsic permeabilities are generally higher in the soy system. Three molecules were significant outliers in the regression metoprolol, quinine, and piroxicam. Metoprolol and quinine are less permeable in the DOPC system than expected, based on their apparent relative lipophilicities and in vivo absorptions [593]. In contrast, piroxicam is more permeable in DOPC than expected based on its relative lipophilicity. With these outliers removed from the regression calculation, the statistics were impressive at r2 0.97. 

Carbamazepine, antipyrine, terbutaline, and hydrochlorothiazide were treated as neutral molecules. Their effective permeabilities were corrected for the unstirred water layer using estimated unstirred water layer permeabilities, determined by the other molecules of similar lipophilicities and size. 

Figure 31 Scheme for the protein-binding, diffusional, and partitioning processes and barriers that are encountered by a highly lipophilic and membrane-interactive drug (D) as it permeates through a cell within a continuous monolayer, h and h, thicknesses of the aqueous boundary layers. kd and ka, dissociation and association binding constants, respectively. P, protein molecule. Permeability coefficients Effective, Pe aqueous boundary layer, PABL and PW apical membrane, Pap basolateral membrane, Pbl. 

Most drugs are ionized in aqueous solution (Table 2.1), and can therefore exist in a neutral or a charged state, depending on the pH of the local environment. Molecules are more lipophilic when neutral than when charged. Ionization is expressed by the aqueous ionization constant, pKa. As pointed out below, log D is a p Independent term for ionizable drugs. Permeability and aqueous solubility are also pKa-dependent. Lipophilicity, pKa, permeability through artificial membranes and... 

Camenisch, G., Alsenz, J., van de Waterbeemd, H., Folkers, G., Estimation of permeability by passive diffusion through Caco-2 cell mono-layers using the drugs lipophilicity and molecular weight, Eur. J. Pharm. Sci. 1998, 6, 313-319. 

Theory and computational aspects of intestinal permeability have been reviewed in detail by Egan and Lauri [27], Briefly, a drug must be somewhat permeable through the membrane of the intestinal tract if it is to be administered orally and achieve systemic exposure. The rate of membrane permeability is strongly related to the lipophilicity and hydrophilicity of the molecule. Thus, models with a small number of descriptors related to those two properties can provide useful predictions of drug absorption. 

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