A method for rapidly predicting drug tissue distribution using surfactant vesicle electrokinetic chromatography

Abstract

Lung tissue distribution of an inhaled drug is important for its potency in the airways and with minimum systemic effects within its dose range. As the lung has the smallest diffusion distance of all the organs in the body and negligible diffusion delays, the characteristics of drug distribution in the lung will mainly depend on drug binding to both tissue and plasma protein. This research aims to develop and evaluate surfactant vesicle electrokinetic chromatography (SEKC) methods for high throughput profile prediction of tissue distribution for inhaled drugs. Several electrokinetic chromatography methods reported in the literature, as well as immobilised artificial membrane chromatography, were compared and evaluated in respect to chromatographic characteristics and statistical correlations. Among these methods, the docusate sodium salt (AOT) SEKC system showed good reproducibility, short run time, and the highest selectivity for alkylphenone test compounds. It also showed a significant statistical correlation between the retention of inhaled drugs and their in vivo volume of distribution at steady-state (V(ss)) in whole human body neglecting the plasma protein-binding differences. Stronger correlations were observed between the AOT SEKC retention of a series of basic drugs and their rat lung tissue-to-plasma water partitioning coefficient (K(pu)), which is affected only by drug binding to the tissue constituent. Further, on comparing correlations between AOT SEKC retention and K(pu) at various rat tissues, it was observed that the strongest correlation was with lung tissue distribution, while the weakest was with brain tissue distribution.

Observed Drug-Receptor Association Rates Are Governed by Membrane Affinity: The Importance of Establishing “Micro-Pharmacokinetic/Pharmacodynamic Relationships” at the β2-Adrenoceptor

“…We cannot exclude the possibility that drug binding to the b 2 -adrenoceptor involves a direct lipid membrane pathway that predominates for highly lipophilic ligands, but what seems certain is that the amphipathic lipid bilayer helps to concentrate lipophilic and suitably charged ligands in the immediate vicinity of the receptor, enhancing the observed association rate, without necessarily suggesting differences in interaction at the receptor. This is supported by literature investigating the kinetics of isomers that share identical logD 7.4 and phospholipid affinity (CHI IAM 7.4 values) (Jiang et al, 2008). Both the S and R-isomers of CGP12177 and pindolol share the same kinetic on-rates but differ only in their measured off-rate (Affolter et al, 1985).…”

“…There was a good correlation between the calculated and measured values (r 2 5 0.91, P , 0.0001), although in most cases logD 7.4 was lower than clogP. To assess the degree of membrane interaction a chromatographic method was applied (Jiang et al, 2008). This method utilizes IAMs consisting of monolayers of phospholipid covalently immobilized on a silica surface, mimicking the lipid environment of a fluid cell membrane on a solid matrix.…”

Electrokinetic chromatographic characterization of novel catanionic surfactants vesicle as pseudostationary phase

“…What is more, instability of the microemulsion owing to pH change, dilution with water or addition of excessive amounts of organic solvent is the biggest problem. Recently, many novel PSPs such as mixed surfactants micelle , surfactant coupled with ionic liquid , polymeric micelle and vesicle appeared. The goal for a new PSP in EKC is to extend elution range, improve selectivity, and enhance separation efficiency.…”