Drug-Induced Phospholipidosis Assays

Apredica provides fast drug-induced phospholipidosis assay turnaround. Contact us to learn more our preclinical ADME Tox CRO services.

Phospholipidosis (PLD) is a lysosomal storage disorder characterized by excessive accumulation of intracellular phospholipids in tissues, such as liver, kidneys, and lungs. It is caused by metabolic dysfunction due to administration of drugs, in particular by cationic amphiphilic drugs. Possible mechanisms of induction of PLD include inhibition of phospholipases due to binding of drug to substrate phospholipases,¹ and binding of drugs to phospholipids, forming complexes that cannot be broken down by phospholipases.² PLD does not necessarily constitute toxicity, and can resolve by itself, but it is predictive of drug or metabolite accumulation in affected tissues that have led to liver, kidney or respiratory failure, and so is of concern to the FDA, which in 2004 formed a PLD Working Group to study the problem.³

Apredica determines drug-induced PLD by measuring the accumulation of a specific fluorescent phospholipid in cells treated with increasing drug concentrations.⁴ This phospholipid is broken down and metabolized by untreated cells, and so fluorescence does not accumulate. When phospholipidosis is induced, the phospholipid does not get broken down and fluorescence accumulates in the cells. A cytotoxicity assay is run in parallel to normalize the amount of accumulation to the number of cells.

Footnotes

1. Reasor MJ and Kacew S. Drug-Induced Phospholipidosis: Are There Functional Consequences? Exp Biol Med (2001) 226:825-830.

2. Vitovic et al. Assessment of drug-lipid complex formation by a high throughput Langmuir balance and correlation to phospholipidosis. J. Medicinal Chemistry (2008) 51:1842-1848.

3. Reasor MJ, Hastings KL and Ulrich RG. Drug-induced phospholipidosis: issues and future directions. Expert Opin Drug Saf. (2006) 5:567-583.

4. Nioi P, Perry BK, Wang E-J, Gu Y-Z and Snyder RG. In vitro detection of drug-induced phospholipidosis using gene expression and fluorescent phospholipid-based methodologies. Toxicol Sci (2007) 99:162-173.