Animals; Cholesterol/metabolism; Chromatography, Micellar Electrokinetic Capillary/methods; Drug-Related Side Effects and Adverse Reactions/diagnosis/pathology; Humans; In Vitro Techniques; Lipidoses/chemically induced/diagnosis; Liposomes; Lysosomes/metabolism; Phospholipids/metabolism; Reproducibility of Results; Risk; Statistics, Nonparametric; Drug phospholipidosis-inducing potential; Liposome electrokinetic chromatography; Phospholipidosis
Abstract :
[en] 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.
Research center :
Centre Interfacultaire de Recherche du Médicament - CIRM
Disciplines :
Pharmacy, pharmacology & toxicology
Author, co-author :
Wang, Tingting
Feng, Ying
Jin, Xiaohan
Fan, Xuxin
Crommen, Jacques ; Université de Liège > Département de pharmacie > Département de pharmacie
Jiang, Zhengjin
Language :
English
Title :
Liposome electrokinetic chromatography based in vitro model for early screening of the drug-induced phospholipidosis risk.
Publication date :
2014
Journal title :
Journal of Pharmaceutical and Biomedical Analysis
ISSN :
0731-7085
eISSN :
1873-264X
Publisher :
Elsevier, Amsterdam, Netherlands
Volume :
96
Pages :
263-71
Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
Copyright (c) 2014 Elsevier B.V. All rights reserved.
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