title: 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.
authors.affiliation: Novartis Institutes for Biomedical Research, Global Discovery Chemistry, Horsham, UK. zhengjin.jiang@novartis.com
authors.forename: Zhengjin
authors.initials: Z
authors.lastname: Jiang
authors.forename: John
authors.initials: J
authors.lastname: Reilly
authors.forename: Brian
authors.initials: B
authors.lastname: Everatt
mesh_terms: D000280:Administration, Inhalation; D020374:Chromatography, Micellar Electrokinetic Capillary / Q000379:methods*; D012015:Reference Standards; D013501:Surface-Active Agents / Q000737:chemistry*; D014018:Tissue Distribution
chemical_list: D013501:Surface-Active Agents