Liposome electrokinetic chromatography based in vitro model for early screening of the drug-induced phospholipidosis risk

摘要

Drug-induced phospholipidosis (PLD) is a storage disorder of lysosomes characterized by the excessive accumulation of phospholipids as a result of improper medical treatments. Although few evidences have supported that PLD can induce significant pathological consequences, this potential toxicity indeed can put off the drug discovery process. In this research, a high-throughput liposome electrokinetic chromatography (LEKC) method was validated to evaluate the PLD risk of drug candidates by screening drug-phospholipid interaction, which correlates to the phospholipidosis inducing risk. A statistical analysis based on the Spearman's correlation test showed that the retention factors (log k) of the tested drugs in the LEKC system and the literature reported in vivo and in vitro PLD data were highly correlated. In order to investigate the predictability of LEKC, the effect of liposome composition such as the molar ratio of phospholipids and the addition of cholesterol were also discussed in this study. The results indicated that the LEKC method could offer a fast, reliable and cost-effective screening tool for early prediction of the PLD inducing potential of drug candidates.