(216ah) Phospholipid:Cholesterol Bilayer Permeability Is Predictable

One of the outstanding problems related to biomembranes is the reliable prediction of the permeability of lipid bilayers.¹  This property is a strong indicator of the ability of molecules to penetrate the cells of any tissue of the body.  As such, its prediction as a function of the molecular structure and properties of the penetrant (molecular weight MW, octanol/water partition coefficient K^oct/w, etc.) is directly relevant to the mechanistic understanding of molecular transport and bioavailability² in such crucial applications as absorption–distribution–metabolism–excretion (ADME) screening of drug candidates,^3,4 and permeability profiling in particular,⁵ as well as risk assessment of chemical exposures through the skin^6-8 and other pathways.⁸  A focus on phospholipids is logical because viable cell membranes are bilayers of such polar lipids (with intercalated cholesterol, membrane proteins and other constituents).^9-12  Although active transport should not be discounted, a focus on passive diffusion is also appropriate "[i]n light of recent conclusions that 80–95% of commercial drugs are absorbed primarily by passive diffusion."⁵

Despite a wealth of permeability data covering numerous phospholipids, wide variations in temperature and cholesterol content, and many permeant species, as well as considerable theoretical understanding, no correlations exist that effectively unify the entire collective database, and permit the direct prediction of passive permeability coefficients P^lip from readily available permeant properties such as MW and K^oct/w.  Part of the difficulty lies in the fact that values of P^lip vary over some ten orders of magnitude in a manner that bears no obvious relation to permeant size or structure.  Adding to the puzzle is an apparent complete disconnect between two types of data sets, namely:

(1) those quantifying variations of P^lip with varying permeant size for a bilayer under given conditions^13,14 (often described using a power law in permeant volume); and

(2) those quantifying variations of P^lip with varying temperature and cholesterol content of the bilayer for a given permeant^15-17 (often described using an exponential function involving permeant projected area).

This poster develops a convenient set of explicit formulas that unify the picture, and describe roughly 100 very diverse data points on fluid-phase bilayer permeability to within an rms error for log₁₀P^lip of only ~0.2.  It is based on a judicious assessment of data on various underlying bilayer properties,^18-21 in addition to permeability per se,^13-17 informed by theoretical arguments.  Permeability data for liquid crystalline phospholipid bilayers composed of egg lecithin, DLPC, DMPC, DPPC and DSPC are analyzed in terms of a mathematical model that accounts for free surface area and chain-ordering effects in the bilayer as well as size and lipophilicity of the permeating species.  Free surface area and chain ordering are largely determined by temperature and cholesterol content of the membrane, molecular size is represented by molecular weight, and lipophilicity of the barrier region is represented by the 1,9-decadiene/water partition coefficient, following earlier work by Xiang, Anderson and coworkers.^13,14,16,22  A correlating variable χ = MWⁿσ/(1-σ) is used to link the results from different membrane systems, where different values of n are tried, and σ denotes a reduced phospholipid density.  The group (1-σ)/σ  is a measure of free surface area, but can also be interpreted in terms of free volume.  A single exponential function of χ is developed that is able to correlate all the observations.  The best fit found for n ~ 0.9 ultimately makes χ much closer to the ratio of molecular to free volumes than surface areas.

A significant advance over previous work²³ is a precise quantification of the effects of bilayer thickness as determined by fatty acid chain length, temperature, and cholesterol content of the bilayer.  The formulas developed serve as a strong starting point for estimating passive permeability of cell membranes to non-ionized solutes as a function of temperature and cholesterol content of the membrane.

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22. Mayer PT, Anderson BD 2002. Transport across 1,9-decadiene precisely mimics the chemical selectivity of the barrier domain in egg lecithin bilayers. J Pharm Sci  91(3):640-646.

23. Nitsche JM, Kasting GB 2013. Permeability of fluid-phase phospholipid bilayers: assessment and useful correlations for permeability screening and other applications. J Pharm Sci http://dxdoiorg/101002/jps23471.