Drug Partitioning: Relationships between Forward and Reverse Rate Constants and Partition Coefficient

Kubjnyi, Hugo

doi:10.1002/jps.2600670237

Cited by 42 publications

(9 citation statements)

References 12 publications

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“…2C) and is consistent with the findings by Hinz et al (32) for phenolic compound transport through hairless mouse skin. This result has been attributed to an underlying transport process where the solute partitions into a series of aqueous and lipid compartments (42,43), rather than partitioning from a lipid membrane to a single aqueous phase. In the present situation, the intercellular lipid polar head groups region and corneocyte matrix provide a polar environment, whereas the lipophilic intercellular lipid tails provide a lipid environment and transport occurs through there in series (Fig.…”

Section: Discussionmentioning

confidence: 79%

“…Previous membrane permeation studies have shown that log J max can be related with log P by a parabolic relationship to recognise that solutes with high log P poorly dissolve in the aqueous phase below the lipid membrane (29)(30)(31)(32)(33)(34)40,41): or a bilinear relationship to describe drug partitioning between a series of aqueous and lipid compartments (42,43):…”

Section: Theorymentioning

confidence: 99%

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Skin Solubility Determines Maximum Transepidermal Flux for Similar Size Molecules

Zhang

Grice

et al. 2009

Pharm Res

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A key finding is that the convex dependence of maximum flux on lipophilicity arises primarily from variations in stratum corneum solubility, and not from diffusional or partitioning barrier effects at the stratum corneum-viable epidermis interface for the more lipophilic phenols. Our data support a solute structure-skin transport model for aqueous solutions in which permeation rates depend on both partitioning and diffusivity: partitioning is related to P, and diffusivity to solute size and hydrogen bonding.

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Section: Discussionmentioning

confidence: 79%

Section: Theorymentioning

confidence: 99%

Skin Solubility Determines Maximum Transepidermal Flux for Similar Size Molecules

Zhang

Grice

et al. 2009

Pharm Res

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“…Experimental observations(620) were quantified as(631) where A t and B t (the subscript “t” denotes the transfer) are empirical coefficients, which are dependent on the organic phase, the geometry of the apparatus, and the stirring rate, but are independent of the molecular structure of the tested chemicals. The rate parameter l i for the transfer from water to the organic phase initially increases with the partition coefficient ( P = l i / l o ) and levels off for high P values.…”

Section: Individual Steps Vs Propertiesmentioning

confidence: 99%

Modeling Kinetics of Subcellular Disposition of Chemicals

Baláž

2009

Chem. Rev.

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“…The fits to experimental data are usually excellent, explaining more than 95% of the variance in the data. 70 They hold for compounds of different structures, for ionizable molecules and ion pairs, 71 and even when measured at different pH values if the distribution coefficients are used. 63 For these reasons, eqs 4 are frequently used in simulations of drug transport in a series of aqueous and nonpolar phases.…”

Section: Resultsmentioning

confidence: 99%

Structural Determinants of Drug Partitioning in n-Hexadecane/Water System

Natesan

Wang

Lukáčová

et al. 2013

J. Chem. Inf. Model.

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Surrogate phases have been widely used as correlates for modeling transport and partitioning of drugs in biological systems, taking advantage of chemical similarity between the surrogate and the phospholipid bilayer as the elementary unit of biological phases, which is responsible for most of transport and partitioning. Solvation in strata of the phospholipid bilayer is an important drug characteristics because it affects the rates of absorption and distribution, as well as the interactions with the membrane proteins having the binding sites located inside the bilayer. The bilayer core can be emulated by n-hexadecane (C16), and the headgroup stratum is often considered a hydrophilic phase because of the high water content. Therefore, we tested the hypothesis that the C16/water partition coefficients (P) can predict the bilayer locations of drugs and other small molecules better than other surrogate systems. Altogether 514 PC16/W values for nonionizable (458) and completely ionized (56) compounds were collected from the literature or measured, when necessary. With the intent to create a fragment-based prediction system, the PC16/W values were factorized into the fragment solvation parameters (f) and correction factors based on the ClogP fragmentation scheme. A script for the PC16/W prediction using the ClogP output is provided. To further expand the prediction system and reveal solvation differences, the fC16/W values were correlated with their more widely available counterparts for the 1-octanol/water system (O/W) using solvatochromic parameters. The analysis for 50 compounds with known bilayer location shows that the available and predicted PC16/W and PO/W values alone or the PC16/O values representing their ratio do not satisfactorily predict the preference for drug accumulation in bilayer strata. These observations indicate that the headgroups stratum, albeit well hydrated, does not have solvation characteristics similar to water and is also poorly described by the O/W partition characteristics.

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Drug Partitioning: Relationships between Forward and Reverse Rate Constants and Partition Coefficient

Cited by 42 publications

References 12 publications

Skin Solubility Determines Maximum Transepidermal Flux for Similar Size Molecules

Skin Solubility Determines Maximum Transepidermal Flux for Similar Size Molecules

Modeling Kinetics of Subcellular Disposition of Chemicals

Structural Determinants of Drug Partitioning in n-Hexadecane/Water System

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