Substituent contributions to the transport of substituted p-toluic acids across lipid bilayer membranes

Article abstract of DOI:10.1002/jps.2600831027

The fluxes of p-toluic acid and seven α-methylene-substituted analogs have been determined as a function of pH across planar egg lecithin/decane bilayers to construct a set of well-isolated polar functional group contributions to the free energy of transfer from water to the bilayer transport barrier domain. Nonlinear regression analyses of flux-pH profiles using a model which accounts for unstirred layer effects yielded membrane permeability coefficients (P(RX)) that varied from 1.1 cm/s for p-toluic acid to 4.1 x 10^-5 cm/s for the α-carbamoyl-p-toluic acid. Bulk organic solvent/water partition coefficients (K(RX)) were obtained for the same set of permeants using four solvent systems to identify a bulk solvent which closely resembles the chemical nature of the bilayer barrier microenvironment for these permeants. The slopes of plots of log P(RX) vs log K(RX) were 0.85, 0.91, 0.99, and 2.4, respectively, for hexadecane/water, hexadecane/water, 1,9-decadiene/water, and octanol/water with the best model solvent being that which yielded a slope closest to unity. A significant deviation in the slope from 1, as observed in the correlation with octanol/water partition coefficients, reveals that this relatively polar, hydrogen-bonding solvent is a poor model solvent for describing the barrier microenvironment for these permeants. Thus, the polar interfacial regions occupied by phospholipid head groups are not the barrier domain for the transport of the series examined in this study. The incremental group contributions to the free energy of transfer to the barrier domain (cal/mol) for the functional groups, Cl, OCH₃, CN, OH, COOH, and CONH₂, were found to be 325, 687, 2170, 3860, 5170, and 6060, respectively. Except for Cl, these group contributions are generally 500-1200 cal/mol smaller than those for transfer between water and hexadecane, resembling most closely the values obtained for transfer from water to 1,9-decadiene.