Structural determinants of drug partitioning in surrogates of phosphatidylcholine bilayer strata

Abstract

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.

Figure 1

Partition coefficients of the studied compounds (Table 2) in the systems C16/DAcPC (full points) and O/W (open points) plotted against those in C16/W system. The compounds not forming H-bonds, H-bond acceptors, and H-bond donors/acceptors are shown in black, blue, and red colors, respectively. Identity line is shown.

Figure 2

Partition coefficients in the DAcPC/W system vs. the C16/W system. The compounds (Table 2) are classified as H-bond acceptors (blue), H-bond donor/acceptors (red), and non-H-bonding molecules (black). The data for compounds with known bilayer location are shown as stars: lipophiles, located in the core, in black, and cephalophiles, located in the headgroups, in red and blue. The lines indicating logP_DAcPC/W = 0 and the identity line are shown.

Figure 3

Comparison of the partition coefficients in the C1 6/O and C16/DAcPC systems. All symbols as in Figure 2. Identity line shown.

Figure 4

Fragment solvation parameters in the DAcPC/W (black), C16/DAcPC (blue), and O/W (red) systems vs. those in the C16/W system. Fragments numbers from Table 4 are shown. Fragment 19 is not plotted because of the missing C16/W value. The zero line and the identity line are shown.

Figure 5

The preferred locations in phosphatidylcholine bilayer plotted as a function of the surrogate partition coefficients. Cephalophiles are shown in red, lipophiles in black, and amphiphiles as combined red-black points. The line for C16/DAcPC corresponds with eq 6 with optimized coefficients.