CATIONIC AMPHIPHILIC DRUG-INDUCED PHOSPHOLIPIDOSIS

Phospholipidosis, a phospholipid storage disorder, defines an excessiv e accumulation of intracellular phospholipids. Phospholipids are struc tural components of mammalian cytoskeleton and cell membranes. The met abolism of this essential cell component is regulated by the individua l cell and may be altered by drugs that interact with phospholipids or the enzymes that affect their metabolism. Xenobiotics or their metabo lites that induce phospholipidosis include a wide variety of pharmacol ogic agents, including antibacterials, antipsychotics, antidepressants , antiarrhythmics, antianginals, antimalarials, anorexic agents, chole sterol-lowering agents, and others. Each of these drugs shares several common physiochemical properties: hydrophobic ring structure on the m olecule and a hydrophilic side chain with a charged cationic amine gro up, hence the class term cationic amphiphilic drugs (CADs). This paper reviews the phospholipid metabolism, physiochemical characteristics o f CADs, specificity of phospholipidosis in animals and humans, functio nal effects of phospholipidosis, interaction of CADs with biologic mem branes and lysosome metabolism, influence of CADs on phospholipases an d phospholipid synthesis, and a proposed mechanism for induction of ph ospholipidosis in the lung. In human risk assessment, investigators sh ould consider the many factors in evaluating a drug that induces phosp holipidosis in animals. These include: the therapeutic class of drug, presence of active metabolites, tissue or organ selectivity in animals and humans, influence of concurrently administered drugs, reversibili ty of effect, and other factors that increase or decrease the inductio n of phospholipidosis. Generalities regarding the etiology, incidence, and effect of the drug on a specific host may not be made. Each drug must be evaluated separately to identify the risk when administered fo r therapeutic effect in humans.