Drug-Induced Phospholipidosis

This chapter focuses on the mechanism and the toxicological implications of drug-induced phospholipidosis (PLD)—a condition in which drugs cause the excessive accumulation of phospholipids in cells. PLD is characterized by the accumulation of phospholipid–drug complexes as intracellular concentric lamellar bodies, which are visible within lysosomes by electron microscopy. Numerous marketed drugs are known to induce PLD in preclinical species at doses that are significantly higher than those routinely prescribed in the clinic. PLD is generally considered to be reversible, but the rate of reversibility varies widely within drugs, tissues, and species. However, PLD is circumstantially associated with toxicities in vivo both preclinically and clinically. In an effort to reduce the risk of drug attrition due to toxicity associated with physicochemical parameters, drug industries are introducing numerous methods that allow companies to select compounds that are less likely to fail for reasons other than the lack of efficacy. To reduce the risk of failure in vivo due to PLD, the methodology has included in silico models and in vitro assays.