Structural Determinants of Drug Partitioning in n-Hexadecane/Water System

Abstract

Surrogate phases have been widely used as correlates for modeling transport and partitioning of drugs in biological systems, taking advantage of chemical similarity between the surrogate and the phospholipid bilayer as the elementary unit of biological phases, which is responsible for most of transport and partitioning. Solvation in strata of the phospholipid bilayer is an important drug characteristics because it affects the rates of absorption and distribution, as well as the interactions with the membrane proteins having the binding sites located inside the bilayer. The bilayer core can be emulated by n-hexadecane (C16), and the headgroup stratum is often considered a hydrophilic phase because of the high water content. Therefore, we tested the hypothesis that the C16/water partition coefficients (P) can predict the bilayer locations of drugs and other small molecules better than other surrogate systems. Altogether 514 PC16/W values for nonionizable (458) and completely ionized (56) compounds were collected from the literature or measured, when necessary. With the intent to create a fragment-based prediction system, the PC16/W values were factorized into the fragment solvation parameters (f) and correction factors based on the ClogP fragmentation scheme. A script for the PC16/W prediction using the ClogP output is provided. To further expand the prediction system and reveal solvation differences, the fC16/W values were correlated with their more widely available counterparts for the 1-octanol/water system (O/W) using solvatochromic parameters. The analysis for 50 compounds with known bilayer location shows that the available and predicted PC16/W and PO/W values alone or the PC16/O values representing their ratio do not satisfactorily predict the preference for drug accumulation in bilayer strata. These observations indicate that the headgroups stratum, albeit well hydrated, does not have solvation characteristics similar to water and is also poorly described by the O/W partition characteristics.

Structural Determinants of Drug Partitioning in Surrogates of Phosphatidylcholine Bilayer Strata

“…For this reason, the published or estimated C16/W 57 and 1-octanol/water (O/W) 42 partition coefficients of all studied compounds are included in Table S1 in Supporting Information. The DAcPC/W partition coefficients were obtained as the C16/W to C16/DAcPC partition coefficient ratios.…”

“…The approximate core-to-headgroup preference is 10 0.218 = 1.65 for the aromatic CH-fragment and more than two times higher, 10 0.598 = 3.96, for the aliphatic CH2-fragment. Using the f C16/W values 57 (Table S3 in Supporting Information), the estimated core-to-water preferences of the aromatic CH-fragment vs the aliphatic CH2-fragment are 10 0.364 = 2.31 and 10 0.682 = 4.81, respectively. In sum, for aromatic CH-fragment as compared to aliphatic CH2-fragment, the water : headgroups : core concentration ratios are 1 : 1.4 : 2.3 and 1 : 1.2 : 4.8, respectively.…”

Estimation of alkane–water logP for neutral, acidic, and basic compounds using an alkylated polystyrene-divinylbenzene high-performance liquid chromatography column

“…A set of structurally diverse solutes (n = 76) comprised of neutral and ionizable acidic and basic compounds was chosen to characterize the gradient and isocratic systems, and data for isocratic log k 50 and gradient t R are reported (Table 1). For most of these compounds (n = 62), reference log P alk values were available from the literature [1,4,[6][7][8]16,[27][28][29][30][31][32][33][34][35], based on shake-flask assays, dual-phase potentiometric titration, water and alkane phase gaseous solubility ratios, or similar experimental methods (Table 1).…”

Aplicação do conceito do par iônico e seus efeitos sobre a lipofilicidade de brometos de amônio quaternários estruturalmente análogos a procaína, com atividade de bloqueio da transmissão neuromuscular, para estudos de <i>(Q)SAR</i>

“…De acordo com a literatura (Kubinyi, 1993;Dearden & Bresnen, 1988;Natesan et al, 2013) (Lombardo, 2008;Natesan et al, 2013;Tsopelas et al, 2016).…”

“…O uso, no entanto, de sistemas alcano/água na partição podem acarretar dificuldades experimentais pelo fato de estes, geralmente, apresentarem alta volatilidade e baixa solubilidade dos compostos, podendo causar "self-associate" dos compostos (Lombardo, 2008;Natesan et al, 2013).…”