Partition coefficients General discussion

It was at the turn of the twentieth century that the importance of lipid solubility in drug action was also independently described by Meyer and Overton (the significance of the oil/water partition coefficient was discussed in Chapter 2). The importance of lipid solubility in drug action subsequently became manifested in the lipoid theory of cellular depression. In essence, this theory correlated a pharmacological effect (e.g., CNS depression) with a physical property (i.e., lipid solubility) rather than a structure-activity relationship. In the process, the theory was attempting to explain the diverse chemical structures that exist within the hypnotic and general anesthetic classes of drugs (see Chapter 11). Today, we realize the limitations of the lipoid theory and appreciate that the distinction between physical and chemical factors is illusory, since chemical structure is a determinant of physical properties. 

As discussed in this chapter, such modelhng studies are, however, currently still subject to considerable imcertainty. As analyzed in detail in [5], the largest uncertainty in the prediction of Joint Persistence and exposure concentrations stems from imcertainty in the prediction of degradation half-fives, which amounts to at least a factor of 5-10. Partition coefficients generally exhibit somewhat lower imcertainties and also tend to be less influential. Fractions of formation, although highly imcertain, are bounded between 0 and 1. As long as the focus is on major transformation products (>10%), the uncertainty in fractions of formation is therefore always below a factor of ten. 

Two macromolecular computational problems are considered (i) the atomistic modeling of bulk condensed polymer phases and their inherent non-vectorizability, and (ii) the determination of the partition coefficient of polymer chains between bulk solution and cylindrical pores. In connection with the atomistic modeling problem, an algorithm is introduced and discussed (Modified Superbox Algorithm) for the efficient determination of significantly interacting atom pairs in systems with spatially periodic boundaries of the shape of a general parallelepiped (triclinic systems). 

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 impact of salt concentration on the formation of micelles has been reported and is in apparent accord with the interfacial tension model discussed in Sect. 4.1, where the CMC is lowered by the addition of simple electrolytes [ 19,65, 280,282]. The existence of a micellar phase in solution is important not only insofar as it describes the behavior of amphipathic organic chemicals in solution, but the existence of a nonpolar pseudophase can enhance the solubility of other hydrophobic chemicals in solution as they partition into the hydrophobic interior of the micelle. A general expression for the solubility enhancement of a solute by surfactants has been given by Kile and Chiou [253] in terms of the concentrations of monomers and micelles and the corresponding solute partition coefficients, giving... 

The study of the coprecipitation of Mg2+ in calcite has been an active area of research, frequently marked by controversy over experimental results and their applicability to natural systems. The literature on this topic is prolific, and we will not attempt to review all of it (for a general review see Mackenzie et al 1983). The literature is divided into studies where direct measurement of the solids formed from solutions have been made, studies where properties of the solids have been inferred from their interactions with solutions (e.g., Schoonmaker et al 1982), and papers where authors have estimated values of the partition coefficient by deduction (e.g., Lahann and Seibert, 1982 Given and Wilkinson, 1985a). Here the discussion will be confined to the experimental studies where the compositions of the solids have been directly determined. 

Examples of structure-resorption correlations using octanol-water partition coefficients as descriptors have been published and are discussed here using several examples. These correlations with log Poet. are generally useful. This is especially true as long as neutral drugs are involved, but values often are imprecise in case of charged drugs. 

Shake-flask measurements are often employed to design a suitable LLPC system for a given sample mixture by assisting in the selection of the two phases in which the compound of interest shows a partition coefficient sufficiently different from those of the impurities. One of the two phases is then immobilized on a suitable support that is packed into the column, and the second phase is used as the mobile phase. In general, partition coefficients of solutes obtained from static experiments compare favorably with those obtained from chromatographic experiments [3]. A comprehensive thermodynamic treatment of LLPC can be found in Ref. 4, and the prediction and control of zone migration is discussed extensively in Ref. 5. 

We report here on the distributions of several chlorobiphenyls In samples of water, sediment and biota of the Acushnet River Estuary - New Bedford Harbor, Buzzards Bay, Massachusetts, U.S.A. Our general objective Is to gain Information of generic utility In addition to providing specific data and Interpretations of assistance to remedial action at this Superfund site. Our specific objectives In this paper are to 1) document the composition of Individual chlorobiphenyls In biota normally harvested by commercial and recreational fishermen and discuss factors which could lead to the observed distributions and potential Implications for public health standards for PCBs In fish and 11) to Investigate, In a preliminary manner, the adherence of bloconcentratlon of PCBs to predictions based on equilibrium assumptions and octanol/water (Kg ) partition coefficients (, 22). 

Once the structure of the PBPK model is formulated, the next step is specifying the model parameters. These can be classified into a chemical-independent set of parameters (such as physiological characteristics, tissue volumes, and blood flow rates) and a chemical-specific set (such as blood/tissue partition coefficients, and metabolic biotransformation parameters). Values for the chemical-independent parameters are usually obtained from the scientific literature and databases of physiological parameters. Specification of chemical-specific parameter values is generally more challenging. Values for one or more chemical-specific parameters may also be available in the literature and databases of biochemical and metabolic data. Values for parameters that are not expected to have substantial interspecies differences (e.g., tissue/blood partition coefficients) can be imputed based on parameter values in animals. Parameter values can also be estimated by conducting in vitro experiments with human tissue. Partitioning of a chemical between tissues can be obtained by vial equilibration or equilibrium dialysis studies, and metabolic parameters can be estimated from in vitro metabolic systems such as microsomal and isolated hepatocyte syterns. Parameters not available from the aforementioned sources can be estimated directly from in vivo data, as discussed in Section 43.4.5. 

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