Structural Determinants of Drug Partitioning in Surrogates of Phosphatidylcholine Bilayer Strata

The knowledge of drug concentrations
in bilayer headgroups, core,
and at the interface between them is a prerequisite for quantitative
modeling of drug interactions with many membrane-bound transporters,
metabolizing enzymes and receptors, which have the binding sites located
in the bilayer. This knowledge also helps understand the rates of
trans-bilayer transport because balanced interactions of drugs with
the bilayer strata lead to high rates, while excessive affinities
for any stratum cause a slowdown. Experimental determination of bilayer
location is so tedious and costly that the data are only available
for some fifty compounds. To extrapolate these valuable results to
more compounds at a higher throughput, surrogate phases have been
used to obtain correlates of the drug affinities for individual strata.
We introduced a novel system, consisting of a diacetyl phosphatidylcholine
(DAcPC) solution with the water content of the fluid bilayer as the
headgroup surrogate and n-hexadecane (C16) representing
the core. The C16/DAcPC partition coefficients were measured for 113
selected compounds, containing structural fragments that are frequently
occurring in approved drugs. The data were deconvoluted into the ClogP-based
fragment solvation characteristics and processed using a solvatochromic
correlation. Increased H-bond donor ability and excess molar refractivity
of compounds promote solvation in the DAcPC phase as compared to bulk
water, contrary to H-bond acceptor ability, dipolarity/polarizability,
and volume. The results show that aromates have more balanced distribution
in bilayer strata, and thus faster trans-bilayer transport, than similar
alkanes. This observation is in accordance with the frequent occurrence
of aromatic rings in approved drugs and with the role of rigidity
of drug molecules in promoting intestinal absorption. Bilayer locations,
predicted using the C16/DAcPC system, are in excellent agreement with
available experimental data, in contrast to other surrogate systems.