Membrane/buffer partition coefficient

In PAMPA measurements each well is usually a one-point-in-time (single-timepoint) sample. By contrast, in the conventional multitimepoint Caco-2 assay, the acceptor solution is frequently replaced with fresh buffer solution so that the solution in contact with the membrane contains no more than a few percent of the total sample concentration at any time. This condition can be called a physically maintained sink. Under pseudo-steady state (when a practically linear solute concentration gradient is established in the membrane phase see Chapter 2), lipophilic molecules will distribute into the cell monolayer in accordance with the effective membrane-buffer partition coefficient, even when the acceptor solution contains nearly zero sample concentration (due to the physical sink). If the physical sink is maintained indefinitely, then eventually, all of the sample will be depleted from both the donor and membrane compartments, as the flux approaches zero (Chapter 2). In conventional Caco-2 data analysis, a very simple equation [Eq. (7.10) or (7.11)] is used to calculate the permeability coefficient. But when combinatorial (i.e., lipophilic) compounds are screened, this equation is often invalid, since a considerable portion of the molecules partitions into the membrane phase during the multitimepoint measurements. 

We analyzed the correlation of the membrane/buffer partition coefficient (Pm/ ) obtained by Roth and Seeman (135) for 14 selected anesthetics with octanol/water partition coefficients (112)... 

Interestingly, Roth and Seeman (135) found that the membrane/ buffer partition coefficient is invariably one fifth of the octanol/water partition coefficient, in disagreement with equation 94. 

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 apparent membrane-buffer partition (distribution) coefficient Kd, defined at... 

Barbato, F. La Rotonda, M. I. Quaglia, E, Interactions of nonsteroidal antiinflammatory drugs with phospholipids comparison between octanol/buffer partition coefficients and chromatographic indexes on immobilized artificial membranes, J. Pharm. Sci. 86, 225-229 (1997). 

The role of the ammonium salt anion is not the loading of the amphipathic weak base per se, but rather to control the stability of loading and the profile and rate of release of the amphipathic weak base from the liposome to the external aqueous phase. Two major factors that differentiate the different anions are, firstly, their ability to induce precipitation/crystallization/ gelation in the intraliposome aqueous phase (1,12), and secondly, their effect on the membrane/buffer and octanol/buffer partition coefficient of the amphipathic weak base (1). Regarding the precipitation, the higher the amount of precipitated amphipathic weak base, the more stable is the loading and the slower is its release rate (10-12,18,33,35) and (Wasserman et al.). There are also some risks involved in the precipitation which in some cases reduce the mechanical stability of the liposomes and change liposome shape (36). 

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. 

Figure 2 ( ) Isopropyl myristate/buffer partition coefficient and (O) permeability coefficient Kof propranolol over a hydrophilic membrane from Tween 60-isopropyl myristate-butanol-water microemulsions with varying octanoic acid/propranolol ratios. (Data from Ref. 18.)...

Ketoprofen, a weak-acid drug, with a pKa 4.12 (25°C, 0.01 M ionic strength), was selected to illustrate Eqs. (7.20) and (7.21) in a series of simulation calculations, as shown in Fig. 7.16. The membrane-buffer apparent partition coefficients /(piii were calculated at various pH values, using the measured constants from... 

Each side of the barrier has a different membrane-buffer apparent partition coefficient Kd, defined at f = oo as... 

The octanol/buffer represents a partition coefficient between two bulk phases it is less affected by the structure of the analyte and therefore it cannot be used to predict the exact value of liposome membrane-to-buffer Xp, which is also affected by the geometry of the analyte (41 4). However, it is accepted and established that the octanol-to-buffer can help to predict transmembrane passive diffusion (40). In the case of liposomes such as Doxil, in which the internal aqueous phase (intraliposome aqueous phase) is different from the external liposome aqueous medium due to large differences in the composition and pH of these two aqueous phases, there are two different liposome membrane-to-aqueous phase partition coefficients this is referred to as asymmetry in the membrane-to-aqueous media partition coefficient. 

Tab. 4.29 1,4-Dihydropyridine partition coefficients into biological membranes and octanol-buffer. (Reprinted from Tab. 1 of ref. 95 with permission from the American Chemical Society)...

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