Partition coefficient artificial membranes

Pauletti, G. M., Wunderli-Allenspach, H. Partition coefficients in vitro Artificial membranes as a standardized distribution model. Bur. J. Pharm. Sci. 1994, 1, 273-282. 

Ong, S. Liu, H. Qiu, X. Bhat, G. Pidgeon, C., Membrane partition coefficients chromatographically measured using immobilized artificial membrane surfaces, Anal. Chem. 67, 755-762 (1995). 

Barbato, F. La Rotonda, M. I. Quaglia, E, Interactions of nonsteroidal antiinflammatory drugs with phospholipids comparison between octanol/buffer partition coefficients and chromatographic indexes on immobilized artificial membranes, J. Pharm. Sci. 86, 225-229 (1997). 

This book is written for the practicing pharmaceutical scientist involved in absorption-distribution-metabolism-excretion (ADME) measurements who needs to communicate with medicinal chemists persuasively, so that newly synthesized molecules will be more drug-like. ADME is all about a day in the life of a drug molecule (absorption, distribution, metabolism, and excretion). Specifically, this book attempts to describe the state of the art in measurement of ionization constants (p Ka), oil-water partition coefficients (log PI log D), solubility, and permeability (artificial phospholipid membrane barriers). Permeability is covered in considerable detail, based on a newly developed methodology known as parallel artificial membrane permeability assay (PAMPA). 

Passive diffusion through the lipid bilayer of the epithelium can be described using the partition coefficient between octanol/water (log P) and A log P (the difference between the partition into octanol/water and heptane/ethylene glycol or heptane/ octanol) [157, 158], The lipophilicity of the drug (log P) (or rather log D at a certain pH) can easily be either measured or calculated, and is therefore generally used as a predictor of drug permeability. Recently, a method using artificial membrane permeation (PAMPA) has also been found to describe the passive diffusion in a similar manner to the Caco-2 cell monolayers [159]. 

Due to their better biomimetic properties, phospholipids have been proposed as an alternative to 1-octanol for lipophiiicity studies. The use of immobilized artificial membranes (lAM) in lipophiiicity determination was recently reviewed and we thus only briefly summarize the main conclusions [108]. lAM phases are silica-based columns with phospholipids bounded covalently. lAM are based on phosphatidylcholine (PC) linked to a silica propylamine surface. Most lipophiiicity studies with lAM were carried out using an aqueous mobile phase with pH values from 7.0 to 7.4 (log D measurements). Therefore, tested compounds were neutral, totally or partially ionized in these conditions. It was shown that the lipophiiicity parameters obtained on I AM stationary phases and the partition coefficients in 1-octanol/water system were governed by different balance of intermolecular interactions [109]. Therefore the relationships between log kiAM and log Poet varied with the class of compounds studied [110]. However, it was shown that, for neutral compounds with log Poet > 1, a correspondence existed between the two parameters when double-chain lAM phases (i.e., lAM.PC.MG and IAM.PC.DD2) were used [111]. In contrast, in the case of ionized compounds, retention on lAM columns and partitioning in 1 -octanol / water system were significantly different due to ionic interactions expressed in lAM retention but not in 1-octanol/water system and due to acidic and basic compounds behaving differently in these two systems. 

The octanol/water partition coefficient (log Poet) is used as a surrogate of the passive transcellular permeation. Ho vever, it has two drawbacks (i) low to moderate correlation with in vivo absorption (ii) time-consuming assay. Therefore, various artificial membrane assays were extensively investigated as alternative approaches with better predictive power and allowing for higher throughput. 

Emollients are often added to cream formulations to modify either the characteristics of the pharmaceutical vehicle or the condition of the skin itself to promote penetration of the active ingredient to act either locally or systemically. The stratum corneum, being keratinized tissue, behaves as a semipermeable artificial membrane, and drug molecules can penetrate by passive diffusion. The rate of drug movement depends on the drug concentration in the vehicle, its aqueous solubility, and the oil/ water partition coefficient between the stratum corneum and the product s vehicle. Commonly used emollients include glycerin, mineral oil, petrolatum, isopropyl pal-mitate, and isopropyl myristate. 

A standardized distribution model using artificial membranes has been developed by Wunderli-Allenspach and coworkers [39, 40]. The apparent partition coefficients of (RS)-propranolol and (S)-dihydroalprenolol were determined in the pH range 2-12 by... 

Similarly, another study on NSAIDs came to the conclusion that the partition coefficients determined on immobilized artificial membranes are more suitable for... 

Ong, S., Liu, H., and Pidgeon, C., Immobilised-artificial-membrane chromatography measurements of membrane partition coefficients and predicting drug membrane permeability, J. Chromatogr. A, 728,113-128, 1996. 

The use of partition coefficients between water and lipophilic media is of wide use in pharmaceutical research. As discussed in the last chapters, different lipophilicity scales are used to describe the lipophilicity of a compound and relate it to its absorption behaviour in vivo. Differences between the logPow and partitioning between phospholipids and water (mainly determined using liposomes) for diverse compounds have been described leading to the development of the immobilized artificial membrane chromatography system. However, also the predictivity of the IAM system is limited and only a small number of membrane systems are available. 

Ong S, Liu H, Pidgeon C. Immobilized artificial membrane chromatography Measurements of membrane partition coefficient and predicting drug membrane permeability. J Chromatogr A 1996 728 113-28. 

Immobilized Artificial Membrane (LAM) packings for HPLC provide a different environment from that of the hydrocarbon-based ODS columns [17,30—32]. In this model, IAMs are purified phospholipids that are covalently bonded to the silicon support. At this time, only IAM columns prepared from phosphatidylcholine are commercially available (Regis Technologies, Inc., Morton Grove, IL). The hypothesis is that the bonded phospholipid layer is akin to the cellular monolayer that represents a barrier to transport. Interaction of the solute with the phospholipid results in a capacity factor ( J that is proportional to the membrane partition coefficient [PCm in Eq. (1)]. In this sense, the IAM approach does not attempt to correlate with literature values of oil water partition coefficients, but seeks to establish a unique membrane interaction parameter. 

A drug is absorbed through diffusion across a series of separate barriers where the single layer of epithelial cells is the most significant barrier to absorption. Many in vitro methods have been developed for the study of this phenomenon. These methods include small animal gut studies, cell culture (i.e., Caco-2 cell culture model), octanol-water partition coefficients, measures of hydrogen bonding and desolvation energies, immobilized artificial membranes, and retention time on reversed-phase HPLC columns. 

Immobilized artificial membranes (lAM) are solid membrane mimetics that are covalently bound to the surface of a silica chromatographic support to generate a phospholipid monolayer. lAM chromatography can be applied to measure membrane partitioning of a given compound or to predict bile salt-membrane interactions they may also be used in studies on transcellular absorption. Artificial membranes appear to be well correlated with 1-octanol/water partition coefficients however, since the latter can be well predicted in silico, the real value of AIMs is the ability to study complex molecules or extracts, where in silico prediction is poor. I AM can also be applied to generate large data sets, that in turn can be applied to train and, therefore, improve in silico models by an extensive data input [41]. 

Fig. 6. Partition coefficients and permeability coefficients of amides as a function of carbon chain length. Dashed hues partition coefficients for (oUve oil + fatty acid)/water system (OOFA) or ether. Solid lines permeabihties across red cell membranes of dog or man, as indicated data from (11 ] or across artificial lipid bilayer membranes, data from Poznansky et al. [25].

Partition/distribution coefficients (logP and D) RP-HPLC logit Shake-flask/HPLC Dual-phase potentiometric titration Octanol coated colunms Liquid artificial membranes... 

Sui X, Sun J, Li H, Wang Y, Liu J, Liu X, Zhang W, Chen L, He Z. 2009. Prediction of volume of distribution values in human using immobilized artificial membrane partitioning coefficients, the fraction of compound ionized and plasma protein binding. Eur J Med Chem 44 4455 460. 

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