Permeability of Fluid-Phase Phospholipid Bilayers: Assessment and Useful Correlations for Permeability Screening and Other Applications

Nitsche, Johannes C. C.; Kasting, Gerald B.

doi:10.1002/jps.23471

Cited by 19 publications

(34 citation statements)

References 107 publications

(351 reference statements)

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“…This general inverse correlation between MW and permeability has been observed previously for small sets of low-MW compounds. 17 However, we could not determine whether the magnitude of the MW penalty observed in our system was consistent with current models. In addition, we observed a bilinear relationship between permeability and lipophilicity.…”

Section: Resultsmentioning

confidence: 58%

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Nonclassical Size Dependence of Permeation Defines Bounds for Passive Adsorption of Large Drug Molecules

et al. 2017

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Macrocyclic peptides are considered large enough to inhibit “undruggable” targets, but the design of passively cell-permeable molecules in this space remains a challenge due to the poorly understood role of molecular size on passive membrane permeability. Using split-pool combinatorial synthesis, we constructed a library of cyclic, per-N-methlyated peptides spanning a wide range of calculated lipohilicities (0 < AlogP < 8) and molecular weights (~800 Da < MW < ~1200 Da). Analysis by the parallel artificial membrane permeability assay revealed a steep drop-off in apparent passive permeability with increasing size in stark disagreement with current permeation models. This observation, corroborated by a set of natural products, helps define criteria for achieving permeability in larger molecular size regimes and suggests an operational cutoff, beyond which passive permeability is constrained by a sharply increasing penalty on membrane permeation.

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Section: Resultsmentioning

confidence: 58%

“…The sharp decrease in log D mem observed in this MW range is not predicted by models with molecular volume dependencies, either in the diffusion term ( V −n ) or in the partition term (exp[− V n ]) (or a combination of both). 28,17,7 …”

Section: Resultsmentioning

confidence: 99%

Nonclassical Size Dependence of Permeation Defines Bounds for Passive Adsorption of Large Drug Molecules

et al. 2017

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“…The values of κ and λ, the size of the lipid vesicle, and the weight percentage of polymers are all comparable to the values observed experiments 5,12,22,23 . In the experiments 24,25 , the permeability coefficients with respect to lipids are measured in the range from 136 × 10 15 mol dyne −1 sec −1 for water to 0.9 × 10 15 mol dyne −1 sec −1 for 1,4-butanediol, and the range of the permeability coefficient for oligomers is about one order of magnitude. The impermeability of polymer to membrane ζ p , is about one order of magnitude and ranges from 1 to 10 k B T, and the adsorption strength represented by η ranges from 0 to -0.1 k B T, which are available from real experiments.…”

Section: Resultsmentioning

confidence: 99%

Wetting transitions within membrane compartments

2014

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A biomimetic membrane in contact with several aqueous phases is theoretically studied using a combination of Helfrich curvature elasticity theory for fluid membranes and self-consistent field theory for polymers in solutions. Two phases that are thermodynamically formed by phase separation of aqueous solutions, as well as stable and metastable shapes of fluid vesicles, have been observed. The wetting transitions from complete to partial wetting and to complete dewetting are identified within a membrane compartment. The dependences of wetting transitions on material parameters, such as the intrinsic contact angles θin, the interaction strengths between the polymers χαβ and between the membrane and the polymer ηp, and impermeability of the membrane to the enclosed polymers ζp, are investigated. For a given χαβ, impermeability ζp and affinity to the membrane ηp, θin is found to be a constant and independent of the reduced volume of vesicles and the volume fraction of two phases.

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“…applications as absorption-distribution-metabolism-excretion (ADME) screening of drug candidates, 1,2 and permeability profiling in particular, 3 as well as risk assessment of chemical exposures through the skin [4][5][6] and other pathways. 6 Through the inclusion of more fluid-phase data, and more crucially also gel-phase data, this paper represents a substantial generalization of a previous analysis of fluid-phase bilayer permeability, 7 henceforth referred to as Part I.…”

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confidence: 99%

“…The analysis is based upon an extensive body of experimental work from the laboratory of Anderson, Xiang and coworkers, and it builds upon important mechanistic deductions made by these authors. The pharmacological literature has seen the devotion of considerable effort [7][8][9][10] to the development of correlations for becauseif reliabletheoretical formulas represent an attractive alternative to experimental assays, which could be carried out for at best a small fraction of the molecules represented in typical lists of drug candidates or chemicals to which the population is exposed. The present analysis constructs a mechanistic description of chain ordering effects as a superstructure upon the backbone of an appropriate measure of lipophilicity of the permeating solute.…”

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confidence: 99%

A Universal Correlation Predicts Permeability Coefficients of Fluid- and Gel-Phase Phospholipid and Phospholipid-Cholesterol Bilayers for Arbitrary Solutes

Nitsche

Kasting

2016

Journal of Pharmaceutical Sciences

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The permeability of gel-phase phospholipids is typically about an order of magnitude lower than that of the same compositions in the fluid phase, yet a quantitative description of the ordering factors leading to this difference has been elusive. The present analysis examines these factors with particular focus on the area per phospholipid chain, Ac, and its relationship to the minimum area per molecule in the crystalline state, A0. It is shown that fluid- and gel-phase phospholipid permeabilities can be reconciled by postulating a minimum area per chain Ac,0 = 17.1 Å(2), substantially less than one would estimate by dividing the accepted value A0 = 40.8 Å(2) by 2. An extended data set of phospholipid and phospholipid-cholesterol bilayer permeability data extending over 9 orders of magnitude is analyzed and correlated according to the developed relationship (N = 85, s = 0.3024, r(2) = 0.9332). Individual permeability values are consequently predicted to within an average deviation of 10(0.3024) or about a factor of 2. The analysis is broadly applicable in the fluid phase but is restricted to gel-phase phospholipid compositions that do not contain cholesterol. Guidance for the latter scenario is provided.

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Permeability of Fluid-Phase Phospholipid Bilayers: Assessment and Useful Correlations for Permeability Screening and Other Applications

Cited by 19 publications

References 107 publications

Nonclassical Size Dependence of Permeation Defines Bounds for Passive Adsorption of Large Drug Molecules

Nonclassical Size Dependence of Permeation Defines Bounds for Passive Adsorption of Large Drug Molecules

Wetting transitions within membrane compartments

A Universal Correlation Predicts Permeability Coefficients of Fluid- and Gel-Phase Phospholipid and Phospholipid-Cholesterol Bilayers for Arbitrary Solutes

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