Membrane/aqueous partition coefficient

The rate of drug absorption for the transeellular route is pH dependent. Sueh dependency results from the fact that the membrane-aqueous partition coefficient for an ionizable drug is pH dependent. 

The lipid-aqueous partition coefficient of a drug molecule affects its absorption by passive diffusion. In general, octanol/pH 7.4 buffer partition coefficients in the 1-2 pH range are sufficient for absorption across lipoidal membranes. However, the absence of a strict relationship between the partition coefficient of a molecule and its ability to be absorbed is due to the complex nature of the absorption process. Absorption across membranes can be affected by several diverse factors that may include the ionic and/or polar characteristics of the drug and/or membrane as well as the site and capacity of carrier-mediated absorption or efflux systems. 

According to Fick s first law of diffusion, the passive diffusion of a drug across a membrane is directly proportional to the membrane-water partition coefficient, provided the interior of the membrane is homogeneous and the concentration of the drug on the receiver side of the membrane is much less than that on the donor side of the membrane, although in practice this linearity does not hold over a very wide range of lipophilicities due to issues such as the presence of aqueous pores in oily membranes, membrane retention of lipophilic molecules, pKa effects, aggregation of the solute, and the unstirred water layer (UWL). 

The toxicity and the affinity of solvents to cell structures increase with hydrophobic properties of solvents, e.g., high toxicities with P, values of l-S. The partition coefficient correlates with the membrane-buffer partition coefficient between membrane and aqueous system. They also depend on membrane characteristics. 

The selectivity of the CHEMFET is determined by the selectivity of the ion receptor in the sensing membrane, the partition coefficients of the different ions over the membrane and aqueous phase and the relative concentrations of the ions in the sample solution. 

Bar suggested that the toxicity in two-phase systems was caused by both the presence of a second phase (phase toxicity) and solvent molecules which dissolved in the aqueous phase (molecular toxicity). Basically, both mechanisms are governed by the same principle in that the solvent accumulates in the microbial membrane. In the case of the direct contact between cells and pure solvent, the rate of entry of solvents in a membrane will be very high. If the solvent has to diffuse via water phase, then the accumulation in membrane will be slower. This latter mechanism on the molecular toxicity has been investigated in more detail. In experiments with liposomes from E. coli, and ten representative organic solvents labeled by under aqueous-saturating levels, it was found that solvents are accumulated preferentially in the cell membrane. The partition coefficients... 

In subsequent studies attempting to find a correlation of physicochemical properties and antimicrobial activity, other parameters have been employed, such as Hammett O values, electronic distribution calculated by molecular orbital methods, spectral characteristics, and hydrophobicity constants. No new insight on the role of physiochemical properties of the sulfonamides has resulted. Acid dissociation appears to play a predominant role, since it affects aqueous solubiUty, partition coefficient and transport across membranes, protein binding, tubular secretion, and reabsorption in the kidneys. An exhaustive discussion of these studies has been provided (10). 

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 ... 

One of the key parameters for correlating molecular structure and chemical properties with bioavailability has been transcorneal flux or, alternatively, the corneal permeability coefficient. The epithelium has been modeled as a lipid barrier (possibly with a limited number of aqueous pores that, for this physical model, serve as the equivalent of the extracellular space in a more physiological description) and the stroma as an aqueous barrier (Fig. 11). The endothelium is very thin and porous compared with the epithelium [189] and often has been ignored in the analysis, although mathematically it can be included as part of the lipid barrier. Diffusion through bilayer membranes of various structures has been modeled for some time [202] and adapted to ophthalmic applications more recently [203,204]. For a series of molecules of similar size, it was shown that the permeability increases with octa-nol/water distribution (or partition) coefficient until a plateau is reached. Modeling of this type of data has led to the earlier statement that drugs need to be both... 

Figure 2.1 Transport model diagram, depicting two aqueous cells separated by a membrane barrier. The drug molecules are introduced in the donor cell. The concentration gradient in the membrane drives the molecules in the direction of the acceptor compartment. The apparent partition coefficient, Kd = 2. [Avdeef, A., Curr. Topics Med. Chem., 1, 277-351 (2001). Reproduced with permission from Bentham Science Publishers, Ltd.]...

The cosolvent may increase the aqueous solubility of the sparingly soluble molecules, which would lower the membrane-donor solution partition coefficient. According to Eq. (2.3), Pe will decrease. Since %R is related to lipophilicity (Section 7.7.2), the retention is also expected to decrease. 

An alternative method to overcome the solubility problem mentioned in the last section is to use bile salts to solubilize lipophilic molecules in the donor wells. Figure 7.51 shows a plot of relative permeability (Pe without bildPe with bile) versus membrane retention, which is related to lipophilicity (Section 7.7.2). As the plot shows, the most lipophilic molecules (carvedilol, propranolol, and verapamil) have attenuated permeabilities (by a factor of 3 in the case of carvedilol). The effective partition coefficient between the PAMPA membrane phase and the aqueous phase containing bile salt micelles [577] is expected to be lower for lipophilic molecules, which should result in lower Pe values. This is evident in the figure. 

In whole tissue or cell monolayer experiments, transcellular membrane resistance (Rm = Pm1) lumps mucosal to serosal compartment elements in series with aqueous resistance (R = P ). The operational definition of Lm depends on the experimental procedure for solute transport measurement (see Section VII), but its magnitude can be considered relatively constant within any given experimental system. Since the Kp range dwarfs the range of Dm, solute differences in partition coefficient dominate solute differences in transcellular membrane transport. The lumped precellular resistance and lumped membrane resistance add in series to define an effective resistance to solute transport ... 

Figure 7 (Left panel) Relative absorption rate for a weak acid (pKa = 3) as a function of mucosal pH for increasing barrier (membrane) permeability (Pb) with fixed unstirred aqueous layer permeability (Pul). X = pHinflectionpoint in Eq. (4). (Right panel) Partition coefficient-dependent absorption rates for salicylic acid and the weak base ephedrine. (From Ref. 19.)...

The un-ionized form is assumed to be sufficiently lipophilic to traverse membranes in the pH-partition hypothesis. If it were not, no transfer could be predicted, irrespective of pH. The lipophilicity of compounds is experimentally determined as the partition coefficient (log P) or distribution coefficient (log D) [16]. The partition coefficient is the ratio of concentrations of the neutral species between aqueous and nonpolar phases, while the distribution coefficient is the ratio of all species between aqueous and nonpolar phases [17,18],... 

Second, P-gp differs from other transporters in that it recognizes its substrates when dissolved in the lipid membrane [52], and not when dissolved in aqueous solution. The site of recognition and binding has been shown to be located in the membrane leaflet facing the cytosol [53, 54], This implies that the membrane concentration of the substrate, Csm, determines activation [57]. Since the nature of a molecular interaction is strongly influenced by the solvent, the lipid membrane must be taken into account as the solvent for the SAR analysis of P-gp. Under certain conditions, the effect of additional solvents or excipients (used to apply hydrophobic substrates or inhibitors) on the lipid membrane and/or on the transporter must also be considered. Lipophilicity of substrates has long been known to play an important role in P-gp-substrate interactions nevertheless, the correlation of the octanol/water partition coefficients with the concentration of half-maximum... 

The partition coefficient KmK is directly related to the free energy of transfer between the aqueous and the membrane phase. The enthalpy and entropy contri-... 

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